JP2023041763A - Fused N-heterocyclic compounds and methods of use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide methods of treating diseases.

SOLUTION: Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, where A, B, E, L¹, R^a, R^b, R^c and the dotted circle are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds, and methods of modulating the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

SELECTED DRAWING: None

COPYRIGHT: (C)2023,JPO&INPIT

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates generally to novel compounds and methods for their preparation and use as therapeutic or prophylactic agents, eg, for the treatment of cancer.

Description of the Related Art RAS represents a group of closely related monomeric globular proteins of 189 amino acids (molecular mass 21 kDa) that associate with the plasma membrane and bind either GDP or GTP. RAS acts as a molecular switch. When the RAS has GDP bound, it is dormant or off-side and "inactive". In response to cellular exposure to certain growth-promoting stimuli, RAS is induced to exchange bound GDP for GTP. GTP binding "switches on" RAS, allowing it to interact with and activate other proteins (its "downstream targets"). The RAS protein itself has a very low endogenous ability to hydrolyze GTP back to GDP, thereby turning off the RAS itself. Switching off RAS requires an exogenous protein called GTPase-activating protein (GAP) that interacts with RAS and greatly facilitates the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAP or convert GTP back to GDP will prolong the activation of that protein, thus signaling the cell to continue growing and dividing. is extended. Overly active RAS signaling can ultimately lead to cancer, as these signals cause cells to grow and divide.

Structurally, RAS proteins contain a G domain responsible for the enzymatic activity of RAS: guanine nucleotide binding and hydrolysis (GTPase reaction). RAS proteins also contain a C-terminal extension region known as the CAAX box, which can be post-translationally modified and is responsible for targeting the RAS protein to the membrane. The G domain is approximately 21-25 kDa in size and contains a phosphate binding loop (P-loop). The P-loop represents the pocket where nucleotides bind in the RAS protein and is a fixed portion of the domain with conserved amino acid residues (glycine 12, threonine 26, and lysine 16) essential for nucleotide binding and hydrolysis. G domains also contain the so-called switch I region (residues 30-40) and switch II region (residues 60-76), both of which are often " It is the dynamic part of the protein that is referred to as the "spring-loaded" mechanism. A key interaction is the hydrogen bond formed by threonine-35 and glycine-60 and the γ-phosphate of GTP, which maintains the switch1 and switch2 regions, respectively, in their active conformations. After hydrolysis of GTP and release of phosphate, the two relax to the inactive GDP conformation.

The most prominent members of the RAS subfamily are HRAS, KRAS, and NRAS, which are primarily involved in many cancer types. ERAS; GEM; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; including RRAS and RRAS2).

Mutations in any one of the three major isoforms of the RAS gene (HRAS, NRAS, or KRAS) are the most common events in human tumorigenesis. About 30% of all human tumors have been found to carry some RAS gene mutation. Surprisingly, KRAS mutations are detected in 25-30% of tumors. By comparison, much lower rates of oncogenic mutations occur in NRAS and HRAS family members (8% and 3%, respectively). The most common KRAS mutations are found at residues G12 and G13 and residue Q61 in the P-loop.

G12C is a frequent mutation in the KRAS gene (glycine-12 to cysteine mutation). This mutation is found in approximately 13% of cancers, approximately 43% of lung cancers, and nearly 100% of MYH-associated polyposis (familial colon cancer syndrome). However, targeting this gene using small molecules is difficult.

Thus, although progress has been made in this field, there remains a need in the art for improved compounds and methods for treating cancer, eg, by inhibiting KRAS, HRAS, or NRAS. The present invention satisfies this need and provides further related advantages.

BRIEF SUMMARY Briefly, embodiments of the present invention provide compounds (stereoisomers, pharmaceutically acceptable salts, tautomers thereof) capable of modulating G12C mutant KRAS, HRAS, and/or NRAS proteins. and prodrugs). In some examples, the compound acts as an electrophile capable of forming a covalent bond with the cysteine residue at position 12 of KRAS, HRAS, or NRAS G12C mutant proteins. Also provided are methods of using such compounds for the treatment of various diseases or conditions, such as cancer.

（式中、Ａ、Ｂ、Ｅ、Ｌ^１、Ｒ^ａ、Ｒ^ｂ、Ｒ^ｃおよび

は、本明細書中で定義の通りである）を有する化合物またはその薬学的に許容され得る塩、立体異性体もしくはプロドラッグを提供する。他の種々の実施形態では、１つまたはそれを超える構造（Ｉ）の化合物および薬学的に許容され得るキャリアを含む薬学的組成物も提供する。 In one embodiment, the following structure (I):

(wherein A, B, E, L ¹ , R ^a , R ^b , R ^c and

is as defined herein) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof. In various other embodiments, pharmaceutical compositions comprising one or more compounds of structure (I) and a pharmaceutically acceptable carrier are also provided.

In another embodiment, the present invention provides a method of treating cancer in a subject in need of a pharmaceutical composition comprising an effective amount of any one or more compounds of structure (I) A method is provided comprising the step of administering to

Another provided method is a method of modulating the activity of a KRAS, HRAS, or NRAS G12C mutant protein, comprising treating the KRAS, HRAS, or NRAS G12C mutant protein with any one of the compounds of structure (I). A method comprising the step of reacting with one. In another embodiment, there is also provided a method of inhibiting proliferation of a cell population comprising contacting the cell population with any one of the compounds of structure (I).

In another embodiment, the invention provides a method of treating a disorder mediated by the G12C mutation of KRAS, HRAS, or NRAS in a subject in need thereof, comprising:
determining whether the subject has a KRAS, HRAS, or NRAS G12C mutation; and if the subject is determined to have a KRAS, HRAS, or NRAS G12C mutation, administering to the subject a therapeutically effective amount of 1 A method comprising administering a pharmaceutical composition comprising one or more compounds of structure (I).

In still further embodiments, the invention provides a method of preparing a labeled KRAS, HRAS or NRAS G12C mutant protein, comprising reacting the KRAS, HRAS or NRAS G12C mutant with a compound of structure (I). obtaining a KRAS, HRAS or NRAS G12C protein labeled with

These and other aspects of the invention will become apparent upon reference to the following detailed description.

DETAILED DESCRIPTION In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the invention. However, one skilled in the art will understand that the invention may be practiced without these details.

Unless the context dictates otherwise, throughout this specification and claims the term "comprises" and variations thereof (such as "comprises" and "comprising") , open-ended, ie, inclusive, such as "including but not limited to".

Throughout this specification, references to "one embodiment" or "an embodiment" mean that the particular property, structure, or feature described in conjunction with the embodiment is at least one embodiment of the invention. are meant to be included in one embodiment. Thus, the phrases "in one embodiment" or "in an embodiment" appearing at various places throughout this specification.
"embodiments" do not necessarily all refer to the same embodiment. Moreover, certain properties, structures, or characteristics may be combined in one or more embodiments in any suitable manner.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

"Amidinyl" refers to a radical of the formula -(C=NR _a )NR _b R _c , where R _a , R _b , and R _c are each independently H or C ₁ -C ₆ alkyl Say.

"Amino" refers to the _-NH2 radical.

"Aminylsulfone" refers to the -S(O) ₂ NH ₂ radical.

"Carboxy" or "carboxyl" refers to the -CO ₂ H radical.

"Cyano" refers to the -CN radical.

"Guanidinyl" has the formula -NR _d (C=NR _a )NR _b R _c , where R _a , R _b , R _c , and R _d are each independently H or C ₁ -C ₆ alkyl is).

"Hydroxy" or "hydroxyl" refers to the -OH radical.

"Imino" refers to the =NH substituent.

"Nitro" refers to the _-NO2 radical.

"Oxo" refers to the =O substituent.

"Thioxo" refers to the =S substituent.

"Alkyl" consists solely of carbon and hydrogen atoms, is saturated or unsaturated (i.e., contains one or more double and/or triple bonds), and contains 1 to 12 carbon atoms (C ₁ to C ₁₂ alkyl), preferably 1 to 8 carbon atoms (C ₁ to C ₈ alkyl), or 1 to 6 carbon atoms (C ₁ to C ₆ alkyl), the remainder of the molecule being monovalent. Refers to straight or branched hydrocarbon chain radicals joined by bonds (e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1 -dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl, propynyl , butynyl, pentynyl, and hexynyl). Alkyl includes alkenyl (one or more carbon-carbon double bonds) and alkynyl (eg, one or more carbon-carbon triple bonds such as ethynyl). "Amidinylalkyl" refers to an alkyl group containing at least one amidinyl substituent. "Guanidinylalkyl" refers to an alkyl group containing at least one guanidinyl substituent. Unless specifically indicated otherwise in the specification, alkyl, amidinylalkyl, and/or guanidinylalkyl groups are optionally substituted.

An “alkylene” or “alkylene chain” consists solely of carbon and hydrogen, is saturated or unsaturated (i.e., contains one or more double bonds and/or triple bonds), and has from 1 to 12 carbon A straight or branched divalent hydrocarbon chain having atoms that connect the remainder of the molecule to a radical group (e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, and n-butynylene, etc.). The alkylene chain is attached to the rest of the molecule via a single or double bond and to the radical group via a single or double bond. The points of attachment of the alkylene chain to the rest of the molecule and radical groups can be through one carbon or any two carbons in the chain. Unless specifically indicated otherwise in the specification, alkylene chains are optionally substituted.

"Alkylcycloalkyl" refers to a radical of the formula -R _b R _d where R _b is cycloalkyl as defined herein and R _d is an alkyl radical as defined above. Unless specifically indicated otherwise in the specification, alkylcycloalkyl groups are optionally substituted.

“Alkoxy” refers to radicals of the formula —OR _a , where R _a is an alkyl radical as defined above containing 1 to 12 carbon atoms. "Amidinylalkyloxy" refers to an alkoxy group containing at least one amidinyl substituent on the alkyl group. "Guanidinylalkyloxy" refers to alkoxy groups containing at least one guanidinyl substituent on the alkyl group. "Alkylcarbonylaminylalkyloxy" refers to an alkoxy group that contains at least one alkylcarbonylaminyl substituent on the alkyl group. "Heterocyclylalkyloxy" refers to an alkoxy group that contains at least one heterocyclyl substituent on the alkyl group. "Heteroarylalkyloxy" refers to an alkoxy group that contains at least one heteroaryl substituent on the alkyl group. "Aminylalkyloxy" means at least one substitution of formula -NR _a R _b (wherein R _a and R _b are each independently H or C ₁ -C ₆ alkyl) on an alkyl group refers to an alkoxy group containing groups. Unless specifically indicated otherwise in the specification, alkoxy groups, amidinylalkyloxy groups, guanidinylalkyloxy groups, alkylcarbonylaminyl groups, heterocyclylalkyloxy groups, heteroarylalkyloxy groups, ) groups, and/or aminylalkyloxy groups are optionally substituted.

"Alkoxyalkyl" is an alkyl radical of the formula -R _b OR _a where R _a is an alkyl radical as defined above containing 1 to 12 carbon atoms and Rb is a radical as defined above containing 1 to 12 carbon atoms. is an alkylene radical). Unless specifically indicated otherwise in the specification, alkoxyalkyl groups are optionally substituted.

"Alkoxycarbonyl" refers to a radical of the formula -C(=O)OR _a where R _a is an alkyl radical as defined above containing from 1 to 12 carbon atoms. Unless specifically indicated otherwise in the specification, an alkoxycarbonyl group is optionally substituted.

"Alkylphosphoryl" refers to a radical of the formula -P(=O)(R _a ), where each R _a is independently an alkyl radical as defined above. Unless specifically indicated otherwise in the specification, alkylphosphoryl groups are optionally substituted.

"Alkylphosphorylaminyl" has the formula -NR _b P(=O)(R _a ), where each R _a is independently an alkyl radical as defined above and R _b is H or is an alkyl radical of). Unless specifically indicated otherwise in the specification, alkylphosphorylaminyl groups are optionally substituted.

"Aryloxy" refers to a radical of the formula -OR _a , where R _a is an aryl radical as defined herein. Unless specifically indicated otherwise in the specification, aryloxy groups are optionally substituted.

"Alkylaminyl" refers to a radical of the formula -NHR _a or -NR _a R _a where each R _a is independently an alkyl radical as defined above containing 1 to 12 carbon atoms. say. A "haloalkylaminyl" group is an alkylaminyl group that contains at least one halo substituent on the alkyl group. A "hydroxylalkylaminyl" group is an alkylaminyl group that contains at least one hydroxyl substituent on the alkyl group. An "amidinylalkylaminyl" group is an alkylaminyl group that contains at least one amidinyl substituent on the alkyl group. A "guanidinylalkylaminyl" group is an alkylaminyl group that contains at least one guanidinyl substituent on the alkyl group. alkylaminyl groups, haloalkylaminyl groups, hydroxylalkylaminyl groups, amidinylalkylaminyl groups, and/or guanidinylalkylaminyl groups, unless specifically indicated otherwise herein is replaced as necessary.

"Aminylalkyl" means an alkyl containing at least one aminyl substituent (-NR _a R _b (wherein R _a and R _b are each independently H or C ₁ -C ₆ alkyl) base. Aminyl substituents can occur on tertiary, secondary, or primary carbons. Unless specifically indicated otherwise in the specification, an aminylalkyl group is optionally substituted.

“Aminylalkylaminyl” refers to a radical of the formula —NR _a R _b where R _a is H or C ₁ -C ₆ alkyl and R _b is aminylalkyl. Unless specifically indicated otherwise in the specification, an aminylalkylaminyl group is optionally substituted.

"Aminylalkoxy" refers to radicals of the formula -OR _a NH ₂ where R _a is alkylene. Unless specifically indicated otherwise in the specification, an aminylalkoxy group is optionally substituted.

"Alkylaminylalkoxy" refers to the formula -OR _a NR _b R _c , where R _a is alkylene and R _b and R _c are each independently H or C ₁ -C ₆ alkyl; with the proviso that one of R _b or R _c is C ₁ -C ₆ alkyl). Unless specifically indicated otherwise in the specification, alkylaminylalkoxy groups are optionally substituted.

"Alkylcarbonylaminyl" refers to a radical of the formula -NH(C=O)R _a , where R _a is an alkyl radical as defined above containing from 1 to 12 carbon atoms. Unless specifically indicated otherwise in the specification, alkylcarbonylaminyl groups are optionally substituted. Alkenylcarbonylaminyls are alkylcarbonylaminyls containing at least one carbon-carbon double bond. Alkenylcarbonylaminyl groups are optionally substituted.

"Alkylcarbonylaminylalkoxy" is a radical of the formula -OR _b NH(C=O)R _a where R _a is an alkyl radical as defined above containing from 1 to 12 carbon atoms and R _b is alkylene. There is a radical). Unless specifically indicated otherwise in the specification, alkylcarbonylaminylalkoxy groups are optionally substituted.

"Alkylaminylalkyl" refers to an alkyl group containing at least one alkylaminyl substituent. Alkylaminyl substituents can be on tertiary, secondary, or primary carbons. Unless specifically indicated otherwise in the specification, alkylaminylalkyl groups are optionally substituted.

"Aminylcarbonyl" refers to a radical of the formula -C(=O)R _a R _b , where R _a and R _b are each independently H or alkyl. Unless specifically indicated otherwise in the specification, an aminylcarbonyl group is optionally substituted.

"Alkylaminylcarbonyl" refers to compounds of the formula -C(=O)NR _a R _b , where R _a and R _b are each independently H or alkyl, provided that R _a or R _b with the proviso that at least one of is alkyl. Unless specifically indicated otherwise in the specification, alkylaminylcarbonyl groups are optionally substituted.

"Aminylcarbonylalkyl" refers to the formula _-RcC (=O) _{NRaRb , where Ra and Rb are} each independently H or alkyl and _Rc is alkylene _. refers to the radical of Unless specifically indicated otherwise in the specification, an aminylcarbonylalkyl group is optionally substituted.

"Aminylcarbonylcycloalkylalkyl" refers to a compound _{of the formula -RcC(=O)NRaRb, where Ra and Rb are each independently H} or alkyl _; is cycloalkyl). Unless specifically indicated otherwise in the specification, an aminylcarbonylcycloalkyl group is optionally substituted.

"Aromatic ring" refers to a cyclic planar portion (ie, a radical) of a molecule having a resonance-bonded ring that exhibits increased stability compared to other bonding arrangements with the same set of atoms. In general, aromatic rings contain a series of covalently bonded coplanar atoms and contain an even number of pi-electrons (e.g., alternating double and single bonds) that are not multiples of 4 (i.e., 4n+2 pi-electrons, n=0,1 , 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, pyrimidyl. Unless specifically indicated otherwise herein, "aromatic ring" includes all optionally substituted radicals.

"Aryl" refers to a carbocyclic ring system radical containing from 6 to 18 carbon atoms and at least one aromatic ring. For the purposes of embodiments of the present invention, an aryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which ring system may be a fused ring system or It may contain bridged ring systems. Aryl radicals include aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene. , and aryl radicals derived from triphenylene. Unless specifically indicated otherwise herein, the term "aryl" or the prefix "ar-" (as in "aralkyl" and the like) is meant to include optionally substituted aryl radicals. means.

"Aralkyl" refers to a radical of the formula -R _b -R _c where R _b is an alkylene chain as defined above and R _c is one or more aryl radicals as defined above. (eg benzyl, diphenylmethyl, etc.). Unless specifically indicated otherwise in the specification, aralkyl groups are optionally substituted.

"Arylalkyloxy" refers to the formula -OR _b -R _c where R _b is an alkylene chain as defined above and R _c is one or more aryl radicals as defined above such as benzyl, diphenyl (e.g., methyl). Unless specifically indicated otherwise in the specification, arylalkyloxy groups are optionally substituted.

“Arylalkylaminyl” refers to compounds of the formula —N(R _a )R _b —R _c , where R _a is H or C ₁ -C ₆ alkyl, R _b is an alkylene chain as defined above, and R _c refers to the radical of one or more aryl radicals as defined above, such as benzyl, diphenylmethyl, and the like. Unless specifically indicated otherwise in the specification, arylalkylaminyl groups are optionally substituted.

"Carboxyalkyl" refers to a radical of the formula -R _b -R _c where R _b is an alkylene chain as defined above and R _c is a carboxyl group as defined above. Unless specifically indicated otherwise in the specification, carboxyalkyl groups are optionally substituted.

"Cyanoalkyl" refers to a radical of the formula -R _b -R _c where R _b is an alkylene chain as defined above and R _c is a cyano group as defined above. Unless specifically indicated otherwise in the specification, cyanoalkyl groups are optionally substituted.

"Carbocyclic" or "carbocycle" refers to a ring system in which each ring atom is carbon.

A "cycloalkyl" or "carbocyclic ring" consists only of carbon and hydrogen atoms, which ring may include fused or bridged ring systems, has from 3 to 15 carbon atoms, preferably refers to a stable non-aromatic monocyclic or polycyclic carbocyclic radical having 3 to 10 carbon atoms, saturated or unsaturated, and attached to the rest of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. A "cycloalkenyl" is a cycloalkyl that contains one or more carbon-carbon double bonds within the ring. Unless specifically indicated otherwise in the specification, cycloalkyl (or cycloalkenyl) groups are optionally substituted.

"Cyanocycloalkyl" refers to a radical of the formula -R _b -R _c where R _b is cycloalkyl and R _c is a cyano group as defined above. Unless specifically indicated otherwise in the specification, cyanocycloalkyl groups are optionally substituted.

"Cycloalkylaminylcarbonyl" refers to compounds of the formula -C(=O)NR _a R _b , where R _a and R _b are each independently H or cycloalkyl with the proviso that R _a or R _b with the proviso that at least one of is cycloalkyl). Unless specifically indicated otherwise in the specification, a cycloalkylaminylcarbonyl group is optionally substituted.

"Cycloalkylalkyl" refers to a radical of the formula -R _b R _d where R _b is an alkylene chain as defined above and R _d is a cycloalkyl radical as defined above. Unless specifically indicated otherwise in the specification, cycloalkylalkyl groups are optionally substituted.

"Fused" refers to any ring structure described herein that is fused to an existing ring structure in the compounds of the invention. When the fused ring is a heterocyclyl or heteroaryl ring, a nitrogen atom replaces any carbon atom on an existing ring structure that is part of the fused heterocyclyl or heteroaryl ring.

"Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

"Haloalkyl" refers to an alkyl radical as defined above substituted with one or more halo radicals as defined above (e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 , 2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl, etc.). "Perhaloalkyl" is an alkyl radical as defined above in which each H atom is replaced with a halogen. Unless specifically indicated otherwise in the specification, haloalkyl groups are optionally substituted.

"Haloalkoxy" refers to radicals of the formula -OR _a , where R _a is a haloalkyl radical, as defined herein, containing 1-12 carbon atoms. Unless specifically indicated otherwise in the specification, haloalkoxy groups are optionally substituted.

A “heterocyclyl” or “heterocyclic ring” has 1 to 12 ring carbon atoms (eg, 2 to 12) and 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. A stable 3- to 18-membered non-aromatic ring radical having Unless specifically indicated otherwise herein, heterocyclyl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which ring systems can include fused ring systems, spiro ring systems (“spiro-heterocyclyl”), and/or bridged ring systems; nitrogen, carbon, or sulfur atoms in the heterocyclyl radical are optionally oxidized; nitrogen Atoms are optionally quaternerized; heterocyclyl radicals are partially or fully saturated. Examples of such heterocyclyl radicals include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoin. drill, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, Including, but not limited to, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. "Heterocyclyloxy" refers to a heterocyclyl group attached through an oxygen linkage (--O--) to the rest of the molecule. "Heterocyclylaminyl" refers to a heterocyclyl group attached to the rest of the molecule through a nitrogen bond (-NR _a -, where R _a is H or C ₁ -C ₆ alkyl). Unless specifically indicated otherwise in the specification, heterocyclyl, heterocyclyloxy, and/or heterocyclylaminyl groups are optionally substituted.

"N-heterocyclyl" refers to a heterocyclyl radical as defined above that contains at least one nitrogen and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless specifically indicated otherwise in the specification, an N-heterocyclyl group is optionally substituted.

"Heterocyclylene" refers to a divalent heterocyclyl group as defined above. Unless specifically indicated otherwise in the specification, heterocyclylene groups are optionally substituted.

"Aminylheterocyclylene" has the formula -N(R _a )R _b -, where R _a is H or C ₁ -C ₆ alkyl and R _b is heterocyclylene as defined above. ) refers to the divalent radical of Unless specifically indicated otherwise in the specification, aminoheterocyclylene groups are optionally substituted.

"Alkylheterocyclylene" refers to a divalent radical of the formula -R _a R _b -, where R _a is alkylene and R _b is heterocyclylene as defined above. Unless specifically indicated otherwise in the specification, alkylheterocyclylene groups are optionally substituted.

"Heteroalkylheterocyclylene" refers to a divalent radical of the formula -R _a R _b -, where R _a is heteroalkylene and R _b is heterocyclylene as defined above. Unless specifically indicated otherwise in the specification, heteroalkylheterocyclylene groups are optionally substituted.

“Heterocyclylalkyl” refers to the formula —R _b R _e where R _b is an alkylene chain as defined above, R _e is a heterocyclyl radical as defined above, and the nitrogen of the heterocyclyl when the heterocyclyl is a nitrogen-containing heterocyclyl atoms are optionally attached to alkyl radicals). Unless specifically indicated otherwise in the specification, heterocyclylalkyl groups are optionally substituted.

“Heterocyclylalkyloxy” refers to the formula —OR _b R _e , where R _b is an alkylene chain as defined above and R _e is a heterocyclyl radical as defined above; A nitrogen atom is optionally attached to an alkyl radical). Unless specifically indicated otherwise in the specification, heterocyclylalkyloxy groups are optionally substituted.

A “heterocyclylalkylaminyl” is a compound of the formula —N(R _c )R _b R _e , where R b is an alkylene chain as defined above, _{R e is} a heterocyclyl radical as defined above, and heterocyclyl is a nitrogen-containing heterocyclyl , where the nitrogen atom of the heterocyclyl is optionally attached to the alkyl radical and R _c is H or C ₁ -C ₆ alkyl). Unless specifically indicated otherwise in the specification, heterocyclylalkyloxy groups are optionally substituted.

"Heteroaryl" means a hydrogen atom, 1 to 13 ring carbon atoms, 1 to 6 ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring containing a heteroatom A 5- to 14-membered ring system radical containing For the purposes of embodiments of the present invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which ring system is a fused can include ring systems or bridged ring systems; nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized; nitrogen atoms can be optionally quaternized, good. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzo dioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4 ,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl , naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (ie, thienyl). "Heteroaryloxy" refers to a heteroaryl group attached to the rest of the molecule through an oxygen linkage (--O--). "Heteroarylaminyl" refers to a heteroaryl group attached to the remainder of the molecule through a nitrogen bond (-NR _a -, where R _a is H or C ₁ -C ₆ alkyl). Unless specifically indicated otherwise in the specification, heteroaryl, heteroaryloxy, and/or heteroarylaminyl groups are optionally substituted.

"N-heteroaryl" refers to a heteroaryl radical as defined above that contains at least one nitrogen and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless specifically indicated otherwise in the specification, N-heteroaryl groups are optionally substituted.

"Heteroarylalkyl" refers to a radical of the formula -R _b R _f where R _b is an alkylene chain as defined above and R _f is a heteroaryl radical as defined above. Unless specifically indicated otherwise in the specification, heteroarylalkyl groups are optionally substituted.

"Heteroarylalkyloxy" refers to the formula -OR _b R _f where R _b is an alkylene chain as defined above and R _f is a heteroaryl radical as defined above, where heteroaryl is a nitrogen-containing heterocyclyl , where the nitrogen atom of the heterocyclyl is optionally attached to the alkyl radical). Unless specifically indicated otherwise in the specification, heteroarylalkyloxy groups are optionally substituted.

"Heteroarylalkylaminyl" refers to compounds of the formula _-NRcRbRf , where _Rb is _an alkylene chain as defined above, _Rf is a heteroaryl radical as defined above, and heteroaryl is a nitrogen- _containing heterocyclyl , where the nitrogen atom of the heterocyclyl is optionally attached to the alkyl radical and R _c is H or C ₁ -C ₆ alkyl). Unless specifically indicated otherwise in the specification, heteroarylalkyloxy groups are optionally substituted. "Hydroxyalkyl" refers to an alkyl group containing at least one hydroxyl substituent. —OH substituents can occur on primary, secondary, or tertiary carbons. Unless specifically indicated otherwise in the specification, hydroxylalkyl groups are optionally substituted. A "hydroxylalkylaminyl" is an alkylaminyl group containing at least one --OH substituent present on a primary, secondary, or tertiary carbon. Unless specifically indicated otherwise in the specification, hydroxylalkylaminyl groups are optionally substituted.

“Phosphate” refers to the group —OP(=O)(R _a )R _b , where R _a is OH, O ⁻ , or OR _c and R _b is OH, O ⁻ , OR _c , or is a further phosphate group (eg, forming a diphosphate or triphosphate) and R _c is a counterion (eg, Na+, etc.).

"Phosphoalkoxy" refers to an alkoxy group as defined herein substituted with at least one phosphate group as defined herein. Unless specifically indicated otherwise in the specification, a phosphoalkoxy group is optionally substituted.

“Thioalkyl” refers to radicals of the formula —SR _a , where R _a is an alkyl radical, as defined above, containing 1-12 carbon atoms. Unless specifically indicated otherwise in the specification, thioalkyl groups are optionally substituted.

As used herein, the term "substituted" means that at least one hydrogen atom (e.g., one, two, three, or all hydrogen atoms) is replaced by a non-hydrogen atom (halogen atom (F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl groups, alkoxy groups, and ester groups; sulfur atoms in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; , alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and trialkylsilyl groups; Any of the above groups (e.g., Alkyl, alkylene, alkylcycloalkyl, alkoxy, alkylphosphoryl, alkylphosphorylaminyl, amidinylalkyloxy, guanidinylalkyloxy, alkylcarbonylaminylalkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, aminylalkyloxy , alkoxyalkyl, alkoxycarbonyl, haloalkylaminyl, hydroxylalkylaminyl, amidinylalkylaminyl, guanidinylalkylaminyl, aminylalkyl, aminylalkylaminyl, aminylalkoxy, alkylaminylalkoxy aryloxy , alkylaminyl, alkylcarbonylaminyl, alkylaminylalkyl, aminylcarbonyl, alkylaminylcarbonyl, alkylcarbonylaminylalkoxy, aminylcarbonylalkyl, aminylcarbonylcycloalkylalkyl, thioalkyl, aryl, aralkyl, arylalkyl oxy, arylalkylaminyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkyloxy, cycloalkylaminyl, cyanocycloalkyl, cycloalkylaminylcarbonyl, cycloalkylalkyl, haloalkyl, haloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclyl aminyl, N-heterocyclyl, heterocyclylalkyl, heterocyclylalkyloxy, heterocyclylalkylaminyl , heteroaryl, N-heteroaryl, heteroarylalkyl, heteroarylalkyloxy, heteroarylalkylaminyl, hydroxylalkylaminyl, phosphoalkoxy, and/or hydroxylalkyl). “Substituted” can also mean that one or more hydrogen atoms are heteroatoms such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. ) is replaced by a higher order bond (eg a double or triple bond). For example, “substituted” includes one or more hydrogen atoms —NR _g R _h , —NR _g C(=O)R _h , —NR _g C(=O)NR _g R _h , —NR _g C(=O)OR _h , -NR _g SO ₂ R _h , -OC(=O)NR _g R _h , -OR _g , -SR _g , -SOR _g , -SO ₂ R _g , -OSO ₂ R Includes any of the above groups replaced by _g , —SO ₂ OR _g , ═NSO ₂ R _g and —SO ₂ NR _g R _h . “Substituted” also means that one or more hydrogen atoms are —C(=O)R _g , —C(=O)OR _g , —C(=O)NR _g R _h , —CH ₂ SO ₂ R _g , —CH ₂ SO ₂ NR _g R means any of the above groups replaced with _h . In the foregoing, R _g and R _h are the same or different and independently hydrogen, alkyl, alkoxy, alkylaminyl, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclyl alkyl, heteroaryl, N-heteroaryl, and/or heteroarylalkyl. "Substituted" further means that one or more hydrogen atoms are aminyl, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylaminyl , thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and/or heteroarylalkyl It means any of the above groups replaced by a bond to the group. Additionally, each of the aforementioned substituents can be optionally substituted with one or more of the above substituents.

Each choice of A, B, E, L, L ¹ , R ^a , R ^d , R ¹ , R ^2a , R ^2b and R ^2c is substituted in all valences unless specifically indicated otherwise. It is understood that the above will be substituted as necessary, provided that . Specifically, each of the A, B, E, L, L ¹ , R ^a , R ^d , R ¹ , R ^2a , R ^2b and R ^2c options is such Optionally substituted (eg, groups such as H and halo are optionally unsubstituted), provided that the substitution results in a stable molecule.

An "electrophile" or "electrophilic moiety" reacts with a nucleophile (e.g., lone pairs, negatively charged, partially negatively charged, and/or moieties with excess electrons, e.g., -SH groups) can be any part. Electrophiles are typically electron deficient or contain an electron deficient atom. In certain embodiments, the electrophile includes a positive or partial positive charge, has a resonance structure that includes a positive or partial positive charge, or has one or more are moieties that result in atoms containing a positive charge or partial positive charge exceeding . In some embodiments, the electrophile contains a conjugated double bond (eg, an α,β-unsaturated carbonyl compound or an α,β-unsaturated thiocarbonyl compound).

The term "effective amount" or "therapeutically effective amount" refers to the amount of a compound described herein sufficient to achieve the intended application, including but not limited to treatment of diseases as defined below. Say. A therapeutically effective amount will vary depending on the intended treatment application (in vivo), or the subject and condition being treated (e.g., the subject's weight and age, the severity of the condition, and the mode of administration, etc.). well, can be readily determined by those skilled in the art. The term also applies to doses that induce a particular response in target cells (eg, decreased platelet adhesion and/or cell migration). Specific dosages will vary depending on the particular compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system possessed.

As used herein, "treatment" or "treating" refers to a beneficial or desirable result (including therapeutic and/or prophylactic benefit) with respect to a disease, disorder, or medical condition. , but not limited to). Therapeutic benefit means eradication or amelioration of the underlying disorder being treated. Therapeutic benefit also includes eradication or amelioration of one or more physiological symptoms associated with the underlying disorder such that improvement is seen in the subject even though the subject may still suffer from the underlying disorder. achieved. In certain embodiments, for prophylactic benefit, the composition is administered to a subject at risk of developing a particular disease or one or more physiological conditions of the disease, even if the disease may not have been diagnosed. Administer to subjects reporting symptoms.

"Therapeutic benefit", as the term is used herein, includes therapeutic and/or prophylactic benefits as described above. A prophylactic effect includes delaying or eliminating the onset of the disease or condition, delaying the onset or eliminating symptoms of the disease or condition, delaying, arresting, or reversing the progression of the disease or condition, or any combination thereof.

The terms "co-administration," "administration in combination with," and grammatical equivalents thereof, as used herein, are the administration of two or more agents to an animal, including humans. and wherein both agents and/or their metabolites are present in the subject at the same time. Co-administration includes co-administration of separate compositions, administration of separate compositions at different times, or administration in a composition in which both agents are present.

"Pharmaceutically acceptable salt" includes both acid and base addition salts.

A "pharmaceutically acceptable acid addition salt" retains the biological effectiveness and properties of the free base, is not biologically or otherwise undesirable, and contains inorganic acids (e.g., hydrochloric acid, bromide, hydrogen acid, sulfuric acid, nitric acid, and phosphoric acid) and organic acids (e.g., acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, horse Uric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1- Hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, (including, but not limited to, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid).

"Pharmaceutically acceptable base addition salt" refers to salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. not. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as Ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline , betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, and resins of polyamines). not. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary amine alkyl halide salts (eg, methyl bromide).

The terms "antagonist" and "inhibitor" are used interchangeably, and these terms inhibit the biological function of a target protein (such as G12C of KRAS, HRAS, or NRAS) by inhibiting the activity or expression of the target protein. A compound that has the ability to Accordingly, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Preferred antagonists herein specifically interact with (e.g., bind to) the target while reducing the biological activity of the target protein by interacting with other members of the signaling pathway of which the target protein is a member. Also specifically included within this definition are compounds that inhibit Favorable biological activities that are inhibited by antagonists are associated with tumor initiation, growth, or expansion.

The term "agonist," as used herein, refers to a compound that has the ability to initiate or enhance the biological function of a target protein by inhibiting the target protein's activity or expression. Accordingly, the term "agonist" is defined in the context of the target polypeptide's biological role. Preferred agonists herein specifically interact with (e.g., bind to) the target, while interacting with other members of the signaling pathway of which the target polypeptide is a member to alter the biology of the target polypeptide. Also specifically included within this definition are compounds that initiate or enhance therapeutic activity.

As used herein, "agent" or "biologically active agent" refers to a biological, pharmaceutical, or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamin derivatives, carbohydrates, toxins, or chemotherapeutic compounds. A variety of compounds can be synthesized, including small molecules and oligomers (eg, oligopeptides and oligonucleotides), and synthetic organic compounds based on a variety of core structures. Additionally, compounds for screening can be obtained from a variety of natural sources, such as plant or animal extracts.

"Signal transduction" is the process by which stimulatory or inhibitory signals are transmitted within or within a cell to elicit an intracellular response. A modulator of a signaling pathway refers to a compound that modulates the activity of one or more cellular proteins that map to the same specific signaling pathway. A modulator can enhance (agonist) or suppress (antagonist) the activity of a signaling molecule.

"Antineoplastic agent," "anti-tumor agent," or "chemotherapeutic agent" refers to any agent useful in the treatment of neoplastic conditions. One anticancer drug class includes chemotherapeutic agents. "Chemotherapy" is one of the administration to cancer patients by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation, or in the form of suppositories. or administration of chemotherapeutic agents and/or other agents.

The term "cell proliferation" refers to the phenomenon of changes in cell number as a result of division. The term also includes cell growth in which the cell's morphology has changed (eg, increased in size) in response to a proliferation signal.

The term "selective inhibition" or "selectively inhibits" means that a biologically active agent is capable of targeting through direct or indirect interaction with the target as compared to off-target signaling activity. Refers to the ability of an agent to preferentially reduce signaling activity.

"Subject" refers to animals such as mammals (eg, humans). The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments the subject is a mammal, and in some embodiments the subject is human.

"Mammal" includes humans and domestic animals (including laboratory and companion animals (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits)) and non-domestic animals (e.g., wild animals). both are included.

"Radiotherapy" involves exposing a subject to radiation emitters (alpha-particle-emitting radionuclides (e.g., actinium and thorium radionuclides), low-energy radiation, using routine methods and compositions known to those of skill in the art). given (LET) radiation emitters (i.e., beta-emitters), conversion electron emitters (such as strontium-89 and samarium-153-EDTMP)), or high-energy radiation (including X-rays, gamma-rays, and neutrons). (including but not limited to).

"Antineoplastic agent," "anti-tumor agent," or "chemotherapeutic agent" refers to any agent useful in the treatment of neoplastic conditions. One class of anticancer agents includes chemotherapeutic agents. "Chemotherapy" means administration of one or more chemotherapeutic agents and/or other agents in various ways (intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, or inhalation). or in the form of suppositories).

"Prodrug" is intended to indicate a compound that can be converted under physiological conditions or by solvolysis into a biologically active compound described herein (e.g., a compound of structure (I)). means. Accordingly, the term "prodrug" refers to a pharmaceutically acceptable precursor to a biologically active compound. In some aspects, a prodrug is inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often confer advantages such as solubility, tissue compatibility, or delayed release in mammals (e.g., Bundgard, H., Design
of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Prodrugs are described in Higuchi, T.; , et al., "Pro-drugs as Novel Delivery Systems," A. et al. C. S. Symposium Series, Vol. 14 and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are fully incorporated herein by reference. The term "prodrug" is also meant to include any covalently bonded carrier that releases an active compound in vivo when such prodrug is administered to a mammalian subject. A prodrug of an active compound, as described herein, is typically active in such a way that the modification is cleaved, either by routine manipulation or in vivo, to the parent active compound. It is prepared by modifying the functional groups present in the compound. Prodrugs include a hydroxy, amino, or mercapto group, which is cleaved to form a free hydroxy, amino, or mercapto group when the prodrug of the active compound is administered to a mammalian subject. includes compounds attached to any group to form each. Examples of prodrugs include, but are not limited to, active compounds containing acetate, formate, and benzoate derivatives of hydroxy functional groups or acetamide, formamide, and benzamide derivatives of amine functional groups, and the like.

（式中、各Ｒ’は、独立して、Ｈまたは必要に応じた置換基であり、ｎは、１、２、３、または４である）のうちの１つを有する化合物が含まれる。 In some embodiments, prodrugs include compounds of structure (I) having phosphate, phosphoalkoxy, ester, or boronic ester substituents. Without wishing to be bound by theory, it is believed that such substituents are converted to hydroxyl groups under physiological conditions. Accordingly, embodiments include any compound disclosed herein in which a hydroxyl group is replaced with a phosphate, phosphoalkoxy, ester, or boronic ester group, e.g., a phosphate or phosphoalkoxy group. . For example, in some embodiments, the hydroxyl group on the R ¹ moiety is replaced with a phosphate, phosphoalkoxy, ester, or boronic ester group, eg, a phosphate or alkoxyphosphate group. Accordingly, exemplary prodrugs of certain embodiments include the following R ¹ moieties:

wherein each R' is independently H or an optional substituent and n is 1, 2, 3, or 4.

The term "in vivo" refers to events that occur within the body of a subject.

Embodiments of the invention disclosed herein also include all pharmaceutical compounds of structure (I) that are isotopically labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers. (ie, “isotopic forms” of the compounds of structure (I)). Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine ( ^2H , ^3H , ^11C , ^13C , respectively). ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I and ¹²⁵ I, etc.). These radiolabeled compounds are used, for example, to help determine or measure compound efficacy by characterizing the site or mode of action, or binding affinity for a pharmacologically important site of action. can be useful. Certain isotopically-labeled compounds of structure (I) (eg, those into which a radioactive isotope is incorporated) are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium (ie, ³ H) and carbon-14 (ie, ¹⁴ C) are particularly useful for this purpose in view of their ease of incorporation and existing means of detection.

Substitution with heavier isotopes, such as deuterium (i.e., ² H), provides certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or decreased dosage requirements). can be obtained and is therefore preferred under some circumstances.

Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, can be useful in Positron Emission Topography (PET) studies for examination of substrate receptor occupancy. Isotopically labeled compounds of structure (I) are generally prepared using suitable isotopically labeled reagents in place of previously used unlabeled reagents, prior art known to those skilled in the art or as described in the Examples below. can be prepared by a process analogous to that of

Certain embodiments are also meant to include in vivo metabolites of the disclosed compounds. Such products can result, for example, from the oxidation, reduction, hydrolysis, amidation, and esterification of the administered compound, primarily by enzymatic processes. Accordingly, embodiments include compounds produced by a process comprising administering a compound of the invention to a mammal for a period of time sufficient to produce a metabolite thereof. Such products are typically administered to animals (such as rats, mice, guinea pigs, monkeys, or humans) with a detectable dose of a radiolabeled compound of the invention, allowing sufficient time for metabolism to occur, The conversion product is identified by isolation from urine, blood, or other biological samples.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

Often crystallizations produce solvates of the compounds of the invention. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of a compound of the invention together with one or more solvent molecules. In some embodiments the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments the solvent is an organic solvent. Accordingly, the compounds of the present invention are hydrates (including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc.) and the corresponding It may exist as solvated forms. In some embodiments, the compounds of the invention are true solvates, while in other cases, the compounds of the invention retain only exogenous water, or water and some exogenous It is a mixture with a solvent.

"As required" or "as required" means that the stated environmental event may or may not occur thereafter, and the statement includes instances where said event or environment does and does not occur means that For example, "optionally substituted aryl" refers to the fact that aryl radicals can be substituted or unsubstituted, and the recitation includes both substituted and unsubstituted aryl radicals. means that

A "pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of biologically active compounds to mammals (eg, humans). Such vehicles include all pharmaceutically acceptable carriers, diluents, or excipients for the compound.

"Pharmaceutically acceptable carrier, diluent, or excipient" means any adjuvant, carrier, excipient, approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals, Glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers. include, but are not limited to:

The compounds of the invention (i.e., compounds of structure (I) and embodiments thereof) or pharmaceutically acceptable salts thereof may contain one or more centers of geometric asymmetry and, therefore, absolute Enantiomers, diastereomers and other stereoisomeric forms defined in terms of stereochemistry as (R) or (S) forms, or in the case of amino acids as (D) or (L) forms can occur. Embodiments therefore include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (−), (R) and (S) isomers, or (D) and (L) isomers are prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques (eg, chromatography and fractional crystallization). Conventional techniques for the preparation/isolation of each enantiomer include chiral synthesis from suitable optically pure precursors or racemate (or racemate (salts or derivatives of). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, it is meant that the compounds include both E and Z geometric isomers. Intend. Likewise, all tautomeric forms are also intended to be included.

Embodiments of the present invention include all rotamers and conformationally restricted forms of the compounds of the present invention. Also included are atropisomers, which are isomers that are isomers that are symmetrical about a single bond, where energy differences due to steric strain or other factors produce a sufficiently high rotational barrier to allow isolation of each conformer. It is a stereoisomer that arises due to hindered rotation. By way of example, certain compounds of the invention may exist as a mixture of atropisomers, or a form in which one atropisomer is purified or enriched in its presence.

In some embodiments, compounds of structure (I) are mixtures of atropisomers. In other embodiments, the compounds of structure (I) are substantially purified atropisomers. In some embodiments, compounds of structure (I) are substantially purified R-atropisomers. In some other embodiments, the compounds of structure (I) are substantially purified S-atropisomers.

A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, including "enantiomers", which are two stereoisomers whose molecules are non-superimposable mirror images of each other. A stereoisomer.

A "tautomer" refers to a proton transfer from one atom of a molecule to another atom of the same molecule. Accordingly, embodiments include tautomers of the disclosed compounds.

The chemical nomenclature protocol and structure diagrams used herein are according to I.G. using the ACD/Name version 9.07 software program and/or the ChemDraw Ultra version 11.0.1 software naming program (CambridgeSoft). U.S.A. P. A. C. It is a modified form of nomenclature. For complex chemical names used herein, substituents are typically named before the group to which they are attached. For example, cyclopropylethyl includes an ethyl backbone with a cyclopropyl substituent. Except for the following, all bonds in chemical structure diagrams herein except all bonds on some carbon atoms that are considered to be attached to enough hydrogen atoms to complete valence Identify.

Compounds In one aspect, the invention provides compounds capable of selectively binding to and/or modulating G12C mutant KRAS, HRAS, or NRAS proteins. Compounds can modulate G12C mutant KRAS, HRAS, or NRAS proteins by reaction with amino acids. Without wishing to be bound by theory, Applicants believe that, in some embodiments, compounds of the present invention, by forming a covalent bond with a cysteine at position 12 of the G12C mutant KRAS, HRAS, or NRAS proteins, reacts selectively with the G12C mutant KRAS, HRAS, or NRAS proteins. By binding to cysteine 12, compounds of the invention can lock the switch II of G12C mutant KRAS, HRAS, or NRAS in an inactive phase. This inactivation step may differ from that observed for KRAS, HRAS, or NRAS bound to GTP and GDP. Some compounds of the invention are also capable of perturbing the conformation of switch I. Some of the compounds of the invention preferentially bind to GDP-bound KRAS, HRAS, or NRAS rather than GTP, thus binding KRAS, HRAS, or NRAS to inactive KRAS, HRAS, or NRAS to GDP. It can sequester in a bound state. Because effector binding to KRAS, HRAS, or NRAS is highly susceptible to switch I and II conformation, irreversible binding of these compounds may disrupt downstream signaling of KRAS, HRAS, or NRAS .

（式中、
Ａは、－Ｌ－Ｒ^１で置換され、Ｒ^２ａ、Ｒ^２ｂおよびＲ^２ｃからなる群から選択される１つ、２つまたは３つのさらなる置換基で必要に応じて置換された５または６員窒素含有ヘテロシクリルまたはヘテロアリールであり；
Ｂは、ＣまたはＮであり；
Ｒ^ａ、Ｒ^ｂおよびＲ^ｃは、各出現において独立して、Ｈ、アミノ、シアノ、ハロ、ヒドロキシル、Ｃ_１～Ｃ_６アルキル、Ｃ_１～Ｃ_６アルキルアミノ、Ｃ_１～Ｃ_６ハロアルキル、Ｃ_１～Ｃ_６アルコキシ、Ｃ_１～Ｃ_６ハロアルコキシ；Ｃ_３～Ｃ_８シクロアルキル、ヘテロシクリルアルキル（ｈｅｔｅｒｏｃｙｃｙｌａｌｋｙｌ）、Ｃ_１～Ｃ_６アルキニル、Ｃ_１～Ｃ_６アルケニル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、アミニルカルボニル、ヘテロアリールまたはアリールであり；
Ｒ^１は、シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールであり；
Ｒ^２ａ、Ｒ^２ｂおよびＲ^２ｃは、各出現において独立して、Ｈ、アミノ、シアノ、ハロ、ヒドロキシル、Ｃ_１～Ｃ_６アルキル、Ｃ_１～Ｃ_６アルキルアミノ、Ｃ_１～Ｃ_６ハロアルキル、Ｃ_１～Ｃ_６アルコキシ、Ｃ_１～Ｃ_６ハロアルコキシ；Ｃ_３～Ｃ_８シクロアルキル、ヘ
テロシクリルアルキル（ｈｅｔｅｒｏｃｙｃｙｌａｌｋｙｌ）、Ｃ_１～Ｃ_６アルキニル、Ｃ_１～Ｃ_６アルケニル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、アミニルカルボニル、ヘテロアリールまたはアリールであり；
Ｌは、各出現において独立して、存在しないか、または－Ｏ－、－ＮＲ^ｄ－、－ＮＲ^ｄＣ（＝Ｏ）－、－ＮＲ^ｄＳ（＝Ｏ）_２－および－Ｓ（＝Ｏ）_２－からなる群から選択されるリンカーであり、ここで、Ｒ^ｄは、ＨまたはＣ_１～Ｃ_６アルキルであり；
Ｌ^１は、アルキレン、ヘテロアルキレン、ヘテロシクリレン、アミニルヘテロシクリレン
アルキルヘテロシクリレンまたはヘテロアルキルヘテロシクリレンであり；

は、芳香環を示し；ならびに
Ｅは、ＫＲＡＳ、ＨＲＡＳまたはＮＲＡＳ Ｇ１２Ｃ変異体タンパク質の１２位のシステイン残基と共有結合を形成することができる求電子部分である）またはその薬学的に許容され得る塩、同位体形態、立体異性体もしくはプロドラッグを有する。 As noted above, in one embodiment of the present invention, compounds are provided that have activity as modulators of G12C mutant KRAS, HRAS or NRAS proteins, wherein the compounds have the following structure (I):

(In the formula,
A is a 5- or 6-membered substituted with -LR ¹ and optionally substituted with 1, 2 or 3 further substituents selected from the group consisting of R ^2a , R ^2b and R ^2c nitrogen-containing heterocyclyl or heteroaryl;
B is C or N;
R ^a , R ^b and R ^c are independently at each occurrence H, amino, cyano, halo, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ haloalkyl, C ₁ - _C6 alkoxy, C1 _{- C6} haloalkoxy; _{C3 - C8} cycloalkyl, heterocyclylalkyl, _{C1 -C6 alkynyl} , C1-C6 alkenyl, aminylalkyl, alkylaminylalkyl , cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
R ¹ is cycloalkyl, heterocyclyl, aryl or heteroaryl;
R ^2a , R ^2b and R ^2c are independently at each occurrence H, amino, cyano, halo, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ haloalkyl, C ₁ - _C6 alkoxy, C1 _{- C6} haloalkoxy; _{C3 - C8} cycloalkyl, heterocyclylalkyl, _{C1 -C6 alkynyl} , C1-C6 alkenyl, aminylalkyl, alkylaminylalkyl , cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
L is independently at each occurrence absent, -O-, -NR ^d -, -NR ^d C(=O)-, -NR ^d S(=O) ₂ - and -S(=O ) ₂ -, wherein R ^d is H or C ₁ -C ₆ alkyl;
L ¹ is alkylene, heteroalkylene, heterocyclylene, aminylheterocyclylene alkylheterocyclylene or heteroalkylheterocyclylene;

represents an aromatic ring; and E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutant protein) or a pharmaceutically acceptable It has salts, isotopic forms, stereoisomers or prodrugs.

L, L ¹ , R ^a , R ^d , R ¹ , R ^2a , R ^2b and R ^2c in compounds of structure (I) are each in a labile structure unless specifically indicated otherwise or or optionally substituted unless it results in improper valence. For example, in some embodiments, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxylalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₃ -C ₈ cycloalkyl, heterocyclylalkyl, C ₁ -C ₆ alkynyl, C ₁ -C ₆ alkenyl, aminylalkyl, alkylaminylalkyl , cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, _C3 - _C8 cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, aryl, alkylene, heteroalkylene, heterocyclylene, alkylheterocyclylene and heteroalkylheterocyclylene are each optionally substituted with one or more substituents.

を有する。Ｌ^１は、所望の結合活性を得るために変わり得る。いくつかの実施形態では、Ｌ^１は、アルキレンまたはヘテロアルキレン、例えばＣ_１～Ｃ_６アルキレンである。他の実施形態では、Ｌ^１は、ヘテロシクリレン、アミニルヘテロシクリレン、アルキルヘテロシクリレンまたはヘテロアルキルヘテロシクリレンである。例えば、いくつかの実施形態では、Ｌ^１はヘテロシクリレンであり、化合物は、以下の構造（Ｉｂ）：

（式中、
Ｇ^１およびＧ^２は、それぞれ独立して、ＮまたはＣＨであり、但し、Ｇ^１およびＧ^２のうちの１つは、Ｎであり；
Ｒ^３ａおよびＲ^３ｂは、各出現において独立して、Ｈ、－ＯＨ、－ＮＨ_２、－ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１～Ｃ_６アルキル、Ｃ_１～Ｃ_６ハロアルキル、Ｃ_１～Ｃ_６ハロアルコキシ、Ｃ_１～Ｃ_６アルキニル、ヒドロキシルアルキル（ｈｙｄｒｏｘｙｌａｌｋｌｙ）、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキルまたはアミニルカルボニルであるか；またはＲ^３ａとＲ^３ｂとは一緒になって、オキソ、炭素環式環または複素環式環を形成するか；またはＲ^３ａは、Ｈ、－ＯＨ、－ＮＨ_２、－ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１～Ｃ_６アルキル、Ｃ_１～Ｃ_６ハロアルキル、Ｃ_１～Ｃ_６ハロアルコキシ、Ｃ_１～Ｃ_６アルキニル、ヒドロキシルアルキル（ｈｙｄｒｏｘｙｌａｌｋｌｙ）、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキルまたはアミニルカルボニルであり、Ｒ^３ｂはＲ^４ｂと一緒になって、炭素環式環または複素環式環を形成し；
Ｒ^４ａおよびＲ^４ｂは、各出現において独立して、Ｈ、－ＯＨ、－ＮＨ_２、－ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１～Ｃ_６アルキル、Ｃ_１～Ｃ_６ハロアルキル、Ｃ_１～Ｃ_６ハロアルコキシ、Ｃ_１～Ｃ_６アルキニル、ヒドロキシルアルキル（ｈｙｄｒｏｘｙｌａｌｋｌｙ）、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキルまたはアミニルカルボニルであるか；またはＲ^４ａとＲ^４ｂとは一緒になって、オキソ、炭素環式環または複素環式環を形成するか；またはＲ^４ａは、Ｈ、－ＯＨ、－ＮＨ_２、－ＣＯ_２Ｈ、ハロ、シアノ、Ｃ_１～Ｃ_６アルキル、Ｃ_１～Ｃ_６ハロアルキル、Ｃ_１～Ｃ_６ハロアルコキシ、Ｃ_１～Ｃ_６アルキニル、ヒドロキシルアルキル（ｈｙｄｒｏｘｙｌａｌｋｌｙ）、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキルまたはアミニルカルボニルであり、Ｒ^４ｂはＲ^３ｂと一緒になって、炭素環式環または複素環式環を形成し；ならびに
ｍ^１およびｍ^２は、それぞれ独立して、１、２または３である）を有する。 In some different embodiments, the compound of structure (I) has the following structure (Ia):

have ^L1 can be varied to obtain the desired binding activity. In some embodiments, L ¹ is alkylene or heteroalkylene, such as C ₁ -C ₆ alkylene. In other embodiments, L ¹ is heterocyclylene, aminylheterocyclylene, alkylheterocyclylene, or heteroalkylheterocyclylene. For example, in some embodiments, L ¹ is heterocyclylene and the compound has the following structure (Ib):

(In the formula,
G ¹ and G ² are each independently N or CH, provided that one of G ¹ and G ² is N;
R ^3a and R ^3b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C _{1 -C 6} haloalkoxy, C ₁ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R ^3a and R ^3b together form an oxo, carbocyclic or heterocyclic ring; or R ^3a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxy alkyl, aminylcarbonylalkyl or aminylcarbonyl, wherein R ^3b together with R ^4b form a carbocyclic or heterocyclic ring;
R ^4a and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C _{1 -C 6} haloalkoxy, C ₁ -C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R ^4a and R ^4b together form an oxo, carbocyclic or heterocyclic ring; or R ^4a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxy alkyl, aminylcarbonylalkyl or aminylcarbonyl, R ^4b taken together with R ^3b form a carbocyclic or heterocyclic ring; and m ¹ and m ² are each independently 1, 2 or 3).

Each of R ¹ , R ^a , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ^4a and R ^4b in compounds of structure (Ib) unless specifically indicated otherwise or if the substitution is Substitution is optional unless it results in an unstable structure or inappropriate valences. For example, in some embodiments, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ in compounds of structure (Ib) haloalkoxy, C ₃ -C ₈ cycloalkyl, heterocyclylalkyl, C ₁ -C ₆ alkynyl, C ₁ -C ₆ alkenyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyano Alkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, carbocyclic, heterocyclic, heteroaryl and aryl groups are each optionally substituted with one or more substituents.

The structure of E is not particularly limited as long as it can form a covalent bond with a nucleophile such as the cysteine residue at position 12 of KRAS, HRAS or NRAS G12C mutant proteins. Thus, moieties that can react with nucleophiles (eg, by covalent bond formation) are preferred. In certain embodiments, E can react with nucleophiles of appropriate reactivity in a conjugate addition manner (eg, 1,4-conjugate addition). In some embodiments, E comprises a conjugated π bond such that electron delocalization results in at least one atom (e.g., a carbon atom) having a positive charge, a partial positive charge, or a polarized bond. . In other embodiments, E is the electronegativity of the two atoms forming the bond such that a partial positive charge is present on one atom (e.g., on a carbon atom) (e.g., due to polarization of the bond). are sufficiently different. E moieties containing carbon-halogen bonds, carbon-oxygen bonds, or carbon bonds to various leaving groups known in the art are examples of such E moieties.

（式中、

は、二重結合または三重結合を表し；
Ｑは、－Ｃ（＝Ｏ）－、－Ｃ（＝ＮＲ^７）－、－ＮＲ^８Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）_２－または－ＮＲ^８Ｓ（＝Ｏ）_２－であり；

が二重結合である場合、Ｒ^５およびＲ^６は、それぞれ独立して、Ｈ、ハロ、シアノ、カルボキシル、Ｃ_１～Ｃ_６アルキル、アルコキシカルボニル、アミニルアルキル、アルキルアミニルアルキル、アリール、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールまたはヒドロキシルアルキルであるか、またはＲ^９とＲ^１０とは一緒になって、炭素環式環、複素環式環またはヘテロアリール環を形成し；

が三重結合である場合、Ｒ^５は存在せず、Ｒ^６は、Ｈ、Ｃ_１～Ｃ_６アルキル、アミニルアルキル、アルキルアミニルアルキルまたはヒドロキシルアルキルであり；
Ｒ^７は、Ｈ、－ＯＨ、－ＣＮまたはＣ_１～Ｃ_６アルキルであり；ならびに
Ｒ^８は、Ｈ、Ｃ_１～Ｃ_６アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、Ｃ_３～Ｃ_８シクロアルキルまたはヘテロシクロアルキルである）を有する。 In certain of the foregoing embodiments, E has the structure:

(In the formula,

represents a double or triple bond;
Q is -C(=O)-, -C(=NR ⁷ )-, -NR ⁸ C(=O)-, -S(=O) ₂ - or -NR ⁸ S(=O) ₂ - can be;

is a double bond, R ⁵ and R ⁶ are each independently H, halo, cyano, carboxyl, C ₁ -C ₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl , heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R ⁹ and R ¹⁰ together form a carbocyclic, heterocyclic or heteroaryl ring;

is a triple bond, R ⁵ is absent and R ⁶ is H, C ₁ -C ₆ alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl;
R ⁷ is H, —OH, —CN or C ₁ -C ₆ alkyl; and R ⁸ is H, C ₁ -C ₆ alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylamino nylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C ₃ -C ₈ cycloalkyl or heterocycloalkyl).

が二重結合である場合、Ｒ^５およびＲ^６は、それぞれ独立して、Ｈ、シアノ、Ｃ_１～Ｃ_６アルキル、アミニルアルキル、アルキルアミニルアルキル、またはヒドロキシルアルキルであるか、またはＲ^５とＲ^６とが一緒になって、炭素環式環または複素環式環を形成する。 In certain embodiments,

is a double bond, R ⁵ and R ⁶ are each independently H, cyano, C ₁ -C ₆ alkyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl, or R ⁵ and ^R6 together form a carbocyclic or heterocyclic ring.

が、二重結合である場合、Ｒ^５およびＲ^６は、それぞれ独立して、Ｈ、シアノ、Ｃ_１～Ｃ_６アルキル、アミニルアルキル、アルキルアミニルアルキル、ヒドロキシルアルキル、カルボキシル、アルコキシカルボニル、ヘテロシクリル、ヘテロシクリルアルキル、アリー
ル、アリールアルキル、ヘテロアリール、またはヘテロアリールアルキルであるか；またはＲ^９とＲ^１０とが一緒になって、炭素環式環または複素環式環を形成する。 In certain other embodiments,

is a double bond, R ⁵ and R ⁶ are each independently H, cyano, C ₁ -C ₆ alkyl, aminylalkyl, alkylaminylalkyl, hydroxylalkyl, carboxyl, alkoxycarbonyl, heterocyclyl , heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; or R ⁹ and R ¹⁰ together form a carbocyclic or heterocyclic ring.

（式中、
Ｑは、－Ｃ（＝Ｏ）－、－Ｃ（＝ＮＲ^７）－、－ＮＲ^８Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）_２－または－ＮＲ^８Ｓ（＝Ｏ）_２－であり；
Ｒ^７は、Ｈ、－ＯＨ、－ＣＮまたはＣ_１～Ｃ_６アルキルであり；
Ｒ^８は、Ｈ、Ｃ_１～Ｃ_６アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、Ｃ_３～Ｃ_８シクロアルキルまたはヘテロシクロアルキルであり；ならびに
Ｒ^９は、電子求引基または脱離基である）を有する。例示的な電子吸引基および脱離基には、隣接する炭素（すなわち、ＱとＲ^１１との間の炭素）が求核攻撃を受けやすくなるように、電気陰性効果、誘起効果および／または共鳴効果によって、この隣接する炭素の部分正電荷を誘起するおよび／または安定化させることができる基（例えば、ハロ、トシル、メシルなど）が含まれる。 In certain other embodiments of the foregoing, E has the structure:

(In the formula,
Q is -C(=O)-, -C(=NR ⁷ )-, -NR ⁸ C(=O)-, -S(=O) ₂ - or -NR ⁸ S(=O) ₂ - can be;
R ⁷ is H, —OH, —CN or C ₁ -C ₆ alkyl;
R ⁸ is H, C ₁ -C ₆ alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C ₃ -C ₈ cycloalkyl or heterocycloalkyl; and R ⁹ is an electron withdrawing or leaving group). Exemplary electron withdrawing and leaving groups include electronegative, ^inductive and/or resonant Included are groups (eg, halo, tosyl, mesyl, etc.) that can induce and/or stabilize the partial positive charge of this adjacent carbon by effect.

In some of the foregoing embodiments, Q is -C(=O)-, -NR ⁸ C(=O)-, -S(=O) ₂ - or -NR ⁸ S(=O) ₂ - be.

In some other aforementioned embodiments, Q is -C(=NR ⁷ )-, where R ⁷ is H, -OH, -CN or C ₁ -C ₆ alkyl. For example, in some embodiments ^R7 is H. In another embodiment, ^R7 is -CN. In another embodiment, ^R7 is -OH.

（式中、

は、二重結合または三重結合を表し；
Ｌ^２は、結合またはアルキレンであり；
Ｑは、－Ｃ（＝Ｏ）－、－Ｃ（＝ＮＲ^７）－、－ＮＲ^８Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）_２－または－ＮＲ^８Ｓ（＝Ｏ）_２－であり；

が二重結合である場合、Ｒ^５およびＲ^６は、それぞれ独立して、Ｈ、ハロ、シアノ、カルボキシル、Ｃ_１～Ｃ_６アルキル、アルコキシカルボニル、アミニルアルキル、アルキルア
ミニルアルキル、アリール、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールまたはヒドロキシルアルキルであるか、またはＲ^５とＲ^６とは一緒になって、炭素環式環、複素環式環またはヘテロアリール環を形成し；

が三重結合である場合、Ｒ^５は存在せず、Ｒ^６は、Ｈ、Ｃ_１～Ｃ_６アルキル、アミニルアルキル、アルキルアミニルアルキルまたはヒドロキシルアルキルであり；
Ｒ^７は、Ｈ、－ＯＨ、－ＣＮまたはＣ_１～Ｃ_６アルキルであり；
Ｒ^８は、Ｈ、Ｃ_１～Ｃ_６アルキル、ヒドロキシルアルキル、アミノアルキル、アルコキシアルキル、アミニルアルキル、アルキルアミニルアルキル、シアノアルキル、カルボキシアルキル、アミニルカルボニルアルキル、Ｃ_３～Ｃ_８シクロアルキルまたはヘテロシクリルアルキルである）を有する。 Thus, in some embodiments, the compound has the following structure (Ic):

(In the formula,

represents a double or triple bond;
L ² is a bond or alkylene;
Q is -C(=O)-, -C(=NR ⁷ )-, -NR ⁸ C(=O)-, -S(=O) ₂ - or -NR ⁸ S(=O) ₂ - can be;

is a double bond, R ⁵ and R ⁶ are each independently H, halo, cyano, carboxyl, C ₁ -C ₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl , heterocyclylalkyl, heteroaryl or hydroxylalkyl, or ^R5 and ^R6 together form a carbocyclic, heterocyclic or heteroaryl ring;

is a triple bond, R ⁵ is absent and R ⁶ is H, C ₁ -C ₆ alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl;
R ⁷ is H, —OH, —CN or C ₁ -C ₆ alkyl;
R ⁸ is H, C ₁ -C ₆ alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C ₃ -C ₈ cycloalkyl or is heterocyclylalkyl).

R, R′, R ^a , R ^b , R ^c , R ^{1 , R 2 ,} R ^3a , R ^3b , R ^{4a , R 4b ,} R ⁵ , R ⁶ , R ⁷ , R ⁸ in compounds of structure (Ic) and ^L2 are each optionally substituted unless specifically indicated otherwise or unless the substitution does not result in an unstable structure or improper valence. For example, in some embodiments, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ in compounds of structure (Ic) haloalkoxy, C ₃ -C ₈ cycloalkyl, heterocyclylalkyl, C ₁ -C ₆ alkynyl, C ₁ -C ₆ alkenyl, hydroxylalkyl, alkoxyalkyl, alkoxycarbonyl, aminoalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, cycloalkyl, heterocyclylalkyl, carbocyclic ring, heterocyclic ring, heteroaryl, aryl and alkylene groups are each one or more optionally substituted with more than .

を有する。 In still more embodiments, the compound has the structure (Id):

have

In some embodiments of compounds of structure (Ib) or (Ic), m ¹ and m ² are both 1. In a different embodiment of compound (Ib) or (Ic), m ¹ and m ² are both 2. In some other different embodiments of compounds of structure (Ib) or (Ic), m ¹ is 2 and m ² is 1.

In some embodiments of compounds of structure (Ib) or (Ic), both G ¹ and G ² are N; in other embodiments G ¹ is CH and G ² is N.

のうちの１つを有する。 In some of the compounds of structure (I), (Ia), (Ib), (Ic) or (Id), A has the structure:

has one of

（式中、Ｒ^２ａは、ＨまたはＣ_１～Ｃ_６アルキルである）のうちの１つを有する。 In some specific embodiments of the foregoing, the compound has the structure (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), ( Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It) or (Iu):

wherein R ^2a is H or C ₁ -C ₆ alkyl.

Each of R ¹ , R ^2a , R ^3a , R ^3b , R ^{4a , R 4b ,} R ⁵ , R ⁶ and L ² in compounds of structures (Ie)-(Iv) unless specifically indicated otherwise , or are optionally substituted unless the substitution does not result in an unstable structure or improper valence. For example, in some embodiments, C ₁ -C ₆ alkyl, aminoalkyl, hydroxylalkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ haloalkyl, C ₁ in compounds of structures (Ie)-(Iv) _-C6 alkoxy, alkoxyalkyl, _{alkoxycarbonyl} , C1- _C6 haloalkoxy; _{C3 - C8} cycloalkyl, heterocyclylalkyl, _C1 - _C6 alkynyl, C1- _C6 alkenyl, aminylalkyl , alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, _C3 - _C8 cycloalkyl, carbocyclic ring, heterocyclic ring, heteroaryl ring, heterocyclyl, heterocyclylalkyl, heteroaryl , aryl and alkylene groups are each optionally substituted unless specifically indicated otherwise.

Without being bound by theory, Applicants believe that the correct choice of R ¹ substituent may play a role in the inhibitory activity of compounds (eg, against G12C of KRAS, HRAS, or NRAS). In some embodiments, R ¹ is aryl or heteroaryl, each of which is optionally substituted with one or more substituents. In some embodiments, ^R1 can reversibly interact with KRAS, HRAS, or NRAS G12C mutant proteins. In some embodiments, ^R1 has high affinity for KRAS, HRAS, or NRAS and exhibits high specificity for KRAS, HRAS, or NRAS of G12C. In some embodiments, ^R1 is capable of hydrophobic interactions with KRAS, HRAS, or NRAS G12C. In some embodiments, ^R1 can form hydrogen bonds with various residues of the KRAS, HRAS, or NRAS proteins of G12C.

In any of the foregoing embodiments, R ¹ is aryl. For example, in some embodiments R ¹ is phenyl, and in other embodiments R ¹ is naphthyl.

In other aforementioned embodiments, R ¹ is heteroaryl, eg, in some embodiments R ¹ is heteroaryl containing one or more ring nitrogen atoms. In more specific embodiments, R ¹ is indazolyl, indolyl, benzimidazole, benzotriazole or quinolinyl.

R ¹ is substituted or unsubstituted. In certain embodiments, R ¹ is substituted with one or more substituents. For example, in some embodiments, R ¹ is halo, amino, hydroxyl, C ₁ -C ₆ alkyl, cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, alkylaminyl, cycloalkyl, heterocyclyl alkyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronate ester, —OC(=O)R, or C ₁ -C ₆ alkylcarbonyloxy, or combinations thereof, wherein R is C ₁ is ~ _C6 alkyl). In different embodiments, R ¹ is substituted with halo, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ alkylcarbonyloxy, or combinations thereof. be done. In different embodiments, R ¹ is substituted with fluoro, chloro, amino, hydroxyl, methyl, isopropyl, cyclopropyl, trifluoromethyl, or methoxy, or combinations thereof. In some even more embodiments, R ¹ is substituted with fluoro, hydroxyl, methyl, isopropyl, trifluoromethyl or methoxy or combinations thereof.

のうちの１つを有する。 In certain embodiments, R ¹ has the structure:

has one of

である。 In some other specific embodiments, R ¹ is

is.

である。 In some of the foregoing embodiments, R ^a is independently at each occurrence H, cyano, —C(=O)NH ₂ ,

is.

である。構造（Ｉｕ）の化合物のいくつかの他の実施形態では、Ｒ^ａは、シアノまたは－Ｃ（＝Ｏ）ＮＨ_２である。構造（Ｉｇｇ）の化合物の異なる実施形態では、Ｒ^ａは、

である。 For example, in some embodiments of compounds of structure (Iy), R ^a is

is. In some other embodiments of compounds of structure (Iu), R ^a is cyano or -C(=O)NH ₂ . In different embodiments of compounds of structure (Igg), R ^a is

is.

Structures (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im) above , (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu) and (Iv), wherein R ^3a , R ^3b , R ^4a and R ^4b are each H; In other embodiments, at least one occurrence of R ^3a , R ^3b , R ^4a or R ^4b is not H. In different embodiments, at least one occurrence of R ^3a , R ^3b , R ^4a or R ^4b is C ₁ -C ₆ alkyl, eg, in some embodiments C ₁ -C ₆ alkyl is , is methyl.

In certain embodiments, R ^3a and R ^3b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, hydroxylalkylly, aminylalkyl, cyanoalkyl , carboxyalkyl or aminylcarbonyl, and R ^4a and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, hydroxyalkylly, aminyl alkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl.

In other aforementioned embodiments, R ^3a and R ^4a are independently at each occurrence H, —OH, hydroxylalkylly, cyano or aminylcarbonyl, and R ^3b and R ^4b are at each occurrence , H.

In certain other embodiments, R ^3a and R ^4a are H at each occurrence and R ^3b and R ^4b are independently at each occurrence H, —OH, —NH ₂ , —CO ₂ H , halo, cyano, hydroxylalkyl, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl.

In any of the foregoing embodiments, at least one occurrence of R ^3a , R ^3b , R ^4a or R ^4b is H and at least one of R ^3a , R ^3b , R ^4a or R ^4b
two occurrences are not H.

In some embodiments, at least one occurrence of R ^3a is —OH, —NH ₂ , —CO ₂ H, halo, cyano, hydroxyalkylly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl; R ^3b , R ^4a and R ^4b are H at each occurrence;

In other aforementioned embodiments, R ^3a and R ^4a are independently at each occurrence H or C ₁ -C ₆ alkyl. In some embodiments, at least one occurrence of R ^3a , R ^4a , R ^3b or R ^4b is independently C ₁ -C ₆ alkyl, such as methyl. In some embodiments, one occurrence of R ^3a is C ₁ -C ₆ alkyl, eg, methyl, and the remaining R ^3a and each R ^4a is H. In some other embodiments, two occurrences of R ^3a are C ₁ -C ₆ alkyl, eg, methyl, and the remaining R ^3a and each R ^4a is H. In some other embodiments, one occurrence of R ^3a and one occurrence of R ^4a are independently C ₁ -C ₆ alkyl, such as methyl, and the remaining R ^3a and R ^4a is H respectively.

In other embodiments, at least one occurrence of R ^4a is —OH, —NH ₂ , —CO ₂ H, halo, cyano, hydroxyalkylly, aminylalkyl, cyanoalkyl, carboxyalkyl or amino nylcarbonyl and R ^3a , R ^3b and R ^4b are H at each occurrence.

In other embodiments, at least one occurrence of R ^3a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, hydroxyalkylly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl and at least one occurrence of R ^3b taken together with R ^4b forms a carbocyclic or heterocyclic ring;

In still more embodiments, at least one occurrence of R ^4a is H, —OH, —NH ₂ , —CO ₂ H, halo, cyano, hydroxyalkylly, aminylalkyl, cyanoalkyl, carboxy is alkyl or aminylcarbonyl and at least one occurrence of ^R4b taken together with ^R3b forms a carbocyclic or heterocyclic ring.

In other embodiments, at least one occurrence of R ^3a and R ^3b are taken together to form a carbocyclic or heterocyclic ring. In other embodiments, at least one occurrence of R ^4a and R ^4b are taken together to form a carbocyclic or heterocyclic ring.

である。他の実施形態では、Ｒ^３ａまたはＲ^４ａのうちの少なくとも１つの出現は、シアノである。他の実施形態では、Ｒ^３ａまたはＲ^４ａのうちの少なくとも１つの出現は、－ＯＨである。他の実施形態では、Ｒ^３ａまたはＲ^４ａのうちの少なくとも１つの出現は、ヒドロキシルアルキル、例えばヒドロキシルメチルである。 In still other embodiments, at least one occurrence of R ^3a or R ^4a is aminylcarbonyl. For example, in certain embodiments, an aminylcarbonyl is

is. In other embodiments, at least one occurrence of ^R3a or ^R4a is cyano. In other embodiments, at least one occurrence of R ^3a or R ^4a is -OH. In other embodiments, at least one occurrence of R ^3a or R ^4a is hydroxylalkyl, eg, hydroxylmethyl.

（式中、
Ｑは、－Ｃ（＝Ｏ）－、－Ｃ（＝ＮＲ^７）－、－ＮＲ^８Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）_２－または－ＮＲ^８Ｓ（＝Ｏ）_２－であり；
Ｒ^５およびＲ^６は、それぞれ独立して、Ｈ、ハロ、シアノ、カルボキシル、Ｃ_１～Ｃ_６アルキル、アルコキシカルボニル、アミニルアルキル、アルキルアミニルアルキル、アリール、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールまたはヒドロキシルアルキルであるか、またはＲ^５とＲ^６とは一緒になって、炭素環式環、複素環式環またはヘテロアリール環を形成し；
Ｒ^７は、Ｈ、－ＯＨ、－ＣＮまたはＣ_１～Ｃ_６アルキルであり；ならびに
Ｒ^８は、Ｈ、Ｃ_１～Ｃ_６アルキルまたはヒドロキシルアルキルである）を有する。 In any of the more foregoing embodiments, E is the structure:

(In the formula,
Q is -C(=O)-, -C(=NR ⁷ )-, -NR ⁸ C(=O)-, -S(=O) ₂ - or -NR ⁸ S(=O) ₂ - can be;
R ⁵ and R ⁶ are each independently H, halo, cyano, carboxyl, C ₁ -C ₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxyl is alkyl, or ^R5 and ^R6 taken together form a carbocyclic, heterocyclic or heteroaryl ring;
R ⁷ is H, —OH, —CN or C ₁ -C ₆ alkyl; and R ⁸ is H, C ₁ -C ₆ alkyl or hydroxylalkyl).

（式中、
Ｑは、－Ｃ（＝Ｏ）－、－ＮＲ^８Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）_２－または－ＮＲ^８Ｓ（＝Ｏ）_２－であり；
Ｒ^６は、Ｈ、Ｃ_１～Ｃ_６アルキル、アミニルアルキル、アルキルアミニルアルキルまたはヒドロキシルアルキルであり；
Ｒ^８は、Ｈ、Ｃ_１～Ｃ_６アルキルまたはヒドロキシルアルキルである）を有する。
Ｑ部分は、典型的には、Ｅの反応性（すなわち、求電子性）を最適化するように選択される。前述の実施形態のいくつかでは、Ｑは、－Ｃ（＝Ｏ）－、－ＮＲ^８Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）_２－または－ＮＲ^８Ｓ（＝Ｏ）_２－である。一定の前述の実施形態では、Ｑは、－Ｃ（＝Ｏ）－である。他の実施形態では、Ｑは、－Ｓ（＝Ｏ）_２－である。さらに多くの実施形態では、Ｑは、－ＮＲ^８Ｃ（＝Ｏ）－である。さらに多くの異なる実施形態では、Ｑは、－ＮＲ^８Ｓ（＝Ｏ）_２－である。 In still any of the other preceding embodiments, E is the following structure:

(In the formula,
Q is -C(=O)-, -NR ⁸ C(=O)-, -S(=O) ₂ - or -NR ⁸ S(=O) ₂ -;
R ⁶ is H, C ₁ -C ₆ alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl;
R ⁸ is H, C ₁ -C ₆ alkyl or hydroxylalkyl).
The Q moiety is typically chosen to optimize the reactivity (ie, electrophilicity) of E. In some of the foregoing embodiments, Q is -C(=O)-, -NR ⁸ C(=O)-, -S(=O) ₂ - or -NR ⁸ S(=O) ₂ - be. In certain of the foregoing embodiments, Q is -C(=O)-. In other embodiments, Q is -S(=O) ₂ -. In more embodiments, Q is -NR ⁸ C(=O)-. In yet many different embodiments, Q is -NR ⁸ S(=O) ₂ -.

In some other aforementioned embodiments, Q is -C(=NR ⁷ )-, where R ⁷ is H, -OH, -CN or C ₁ -C ₆ alkyl. For example, in some embodiments, R ^8' is H. In another embodiment, ^R7 is -CN. In another embodiment, ^R7 is -OH.

In some of the foregoing embodiments, ^R8 is H. In other of these embodiments, R ⁸ is hydroxylalkyl, eg, in some embodiments hydroxylalkyl is 2-hydroxyalkyl.

In any one of the several foregoing embodiments, at least one of ^R5 and ^R6 is H. For example, in some embodiments, ^R5 and ^R6 are each H.

を有する。 In other aforementioned embodiments, ^R6 is alkylaminylalkyl. In some of these embodiments, R ⁶ has the structure:

have

In other embodiments, R ⁶ is hydroxylalkyl, such as 2-hydroxyalkyl.

を有するフェニル環である。 In some other different embodiments of the foregoing embodiments, R ⁵ and R ⁶ together form a carbocyclic ring. For example, in some of these embodiments the carbocyclic ring is a cyclopentene, cyclohexene or phenyl ring. In other embodiments, the carbocyclic ring is a cyclopentene or cyclohexene ring. In other embodiments, the carbocyclic ring is a phenyl ring, such as the structure:

is a phenyl ring with

のうちの１つを有する。 In any of some of the foregoing embodiments, E is an electrophile capable of binding a KRAS, HRAS or NRAS protein containing the G12C mutation. In some embodiments, electrophile E can form an irreversible covalent bond with a G12C mutant KRAS, HRAS or NRAS protein. In some cases, electrophile E can bind to the cysteine residue at position 12 of the G12C mutant KRAS, HRAS or NRAS protein. In various embodiments of any of the foregoing, E has the structure:

has one of

のうちの１つを有する。 In other embodiments of any of the foregoing, E has the structure:

has one of

のうちの１つを有する。 In different embodiments, E is the structure:

has one of

（式中、
Ｒ^８は、ＨまたはＣ_１～Ｃ_６アルキルであり；
Ｒ^５は、Ｈ、シアノまたはＣ_１～Ｃ_６アルキルであるか、またはＲ^５はＲ^６と一緒になって、炭素環式環を形成し；
Ｒ^６は、ＨまたはＣ_１～Ｃ_６アルキルであるか、またはＲ^６はＲ^５と一緒になって、炭素環式環を形成し、ならびに
Ｒ^６ａは、ＨまたはＣ_１～Ｃ_６アルキルである）のうちの１つを有する。 In some cases, E has the structure:

(In the formula,
R ⁸ is H or C ₁ -C ₆ alkyl;
R ⁵ is H, cyano or C ₁ -C ₆ alkyl, or R ⁵ together with R ⁶ forms a carbocyclic ring;
R ⁶ is H or C ₁ -C ₆ alkyl, or R ⁶ together with R ⁵ forms a carbocyclic ring and R ^6a is H or C ₁ -C ₆ alkyl have one of

である。いくつかの実施形態では、Ｅは、

である。いくつかの実施形態では、Ｅは、

である。 In some embodiments, E is

is. In some embodiments, E is

is. In some embodiments, E is

is.

^L2 can be selected to provide proper spacing and/or orientation for the E group to form a bond with the KRAS, HRAS or NRAS protein. In some of the foregoing embodiments, ^L2 is a bond. In other aforementioned embodiments, L ² is alkylene. In some embodiments, the alkylene is substituted. In other embodiments, the alkylene is unsubstituted. For example, in some embodiments, L ² is CH ₂ or CH ₂ CH ₂
is.

In any of the foregoing embodiments, L is absent. In other embodiments, L is -O-, -NH-, -NHC(=O)-, -NHS(=O) ₂ - or -S(=O) ₂ -.

Some embodiments of compounds contain more than one stereoisomer. Other embodiments are directed to single stereoisomers. In some embodiments, the compounds are racemates (e.g., mixtures of atropisomers); in other embodiments, the compounds are substantially single isomers, e.g., substantially purified atropisomers. is the body. In some embodiments, the compound is a substantially purified S-atropisomer. In some different embodiments, the compound is a substantially purified R-atropisomer.

ＮＤ＝未決定 In various different embodiments, the compound has one of the structures set forth in Table 1 below. Experimental mass spectrometry data are included in Table 1. Exemplary synthetic procedures are known in the art and are described in more detail below and in the Examples.

ND=not determined

It is understood herein that combinations of substituents and/or variables of the formulas described are permissible only if such contributions result in stable compounds.

In addition, all compounds of the present invention that exist in free base or free acid form can be converted to pharmaceutically acceptable salts thereof by treatment with a suitable inorganic or organic base or acid by methods known to those skilled in the art. can be converted. Salts of the compounds of the invention can be converted to their free base or free acid forms by standard techniques.

Exemplary compounds of structure (I) were prepared according to methods analogous to those illustrated in the examples below. It is understood that these compounds may be made by those skilled in the art by similar methods or by combining other methods known to those skilled in the art. Other compounds of structure (I) not specifically exemplified below can be prepared in a manner analogous to that described below by using the appropriate starting components and modifying the synthetic parameters as necessary. It is also understood that one skilled in the art may be able to make them. Generally, starting components are obtained from Sigma Aldrich, Lancaster Synthesis, Inc.; , Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or synthesized according to sources known to those skilled in the art (e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or as described in the present invention.

Furthermore, those skilled in the art will recognize that certain modifications of the above schemes and schemes provided in the examples enable the preparation of different embodiments of compounds of structure (I). Those skilled in the art will also recognize that in the process of preparing compounds described herein, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include, but are not limited to, hydroxy, amino, mercapto, and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (eg, t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include -C(O)-R'' (where R'' is alkyl, aryl, or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include alkyl esters, aryl esters or arylalkyl esters. Protecting groups are added or removed as necessary according to standard techniques known to those skilled in the art and described herein. The use of protecting groups is described in Green, T.; W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed. , Wiley. As those skilled in the art will recognize, the protecting group can also be a polymeric resin such as Wang resin, Rink resin, or 2-chlorotrityl-chloride resin.

One skilled in the art will recognize that such protected derivatives of the compounds of the present invention may not themselves possess pharmacological activity, but administering the derivatives to a mammal will produce a pharmacologically active compound of the present invention after metabolism in the body. It will also be recognized that it is possible to form Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds of the invention are included within the scope of the invention.

Pharmaceutical Compositions Other embodiments relate to pharmaceutical compositions. Pharmaceutical compositions comprise any one (or more) of the compounds described above and a pharmaceutically acceptable carrier. In some embodiments, pharmaceutical compositions are formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still further embodiments, pharmaceutical compositions comprise a compound disclosed herein and an additional therapeutic agent (eg, an anti-cancer agent). Non-limiting examples of such therapeutic agents are described herein below.

Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, aural, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracerebroventricular, intraperitoneal, intralymphatic, and intranasal injection. included.

In certain embodiments, the compounds described herein are administered locally rather than in a systemic manner, for example via direct injection of the compound into an organ, often in a depot or sustained release formulation. In certain embodiments, long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, such as a liposome coated with an organ-specific antibody. In such embodiments, the liposomes are targeted to and selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of rapid release, extended release, or intermediate release formulations. In still other embodiments, the compounds described herein are administered topically.

The compounds of the invention are effective over a wide dosage range. For example, for adult treatment, dosages of 0.01-1000 mg/day, 0.5-100 mg/day, 1-50 mg/day, and 5-40 mg/day are used in some embodiments. is an example of An exemplary dosage is 10-30 mg/day. The precise dosage will depend on the route of administration, the form in which the compound is administered, the subject to be treated, the weight of the subject to be treated, and the preferences and experience of the attending physician.

In some embodiments, the compounds of the invention are administered in a single dose. Typically, such administration for rapid introduction of drugs is by injection (eg, intravenous injection). However, other routes are used if necessary. A single dose of the compounds of the invention may also be used for treatment of acute conditions.

In some embodiments, the compounds of the invention are administered in multiple doses. In some embodiments, administration is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, administration is about once a month, once every two weeks, once a week, once every other day. In another embodiment, a compound of this invention and another agent are administered together from about 1 time/day to about 6 times/day. In another embodiment, administration of compounds and agents of the invention continues for less than about 7 days. In yet other embodiments, administration continues for more than about 6 days, 10 days, 14 days, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous dosing is given and maintained as long as necessary.

Administration of the compounds of the invention can be continued as long as necessary. In some embodiments, the compounds of the invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the invention are administered continuously over a long period of time, eg, for treatments that have a chronic effect.

In some embodiments, the compounds of the invention are administered in multiple doses. It is known in the art that individualization of dosing regimens is necessary for optimal therapy due to the variability in the pharmacokinetics of compounds between subjects. Dosing regimens for the compounds of the invention can be found through routine experimentation in light of the present disclosure.

In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In certain embodiments, the pharmaceutical composition comprises one or more physiologically active compounds comprising excipients and adjuvants that facilitate processing of the active compound into preparations that can be used pharmaceutically. It is formulated in a conventional manner using acceptable carriers. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as appropriate in formulating the pharmaceutical compositions described herein. Remington: The
Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.; , Remington's Pharmaceutical Sciences, Mack Publishing Co.; , Easton, Pennsylvania 1975; A. and Lachman, L.; , Eds. , Pharmaceutical Dosage Forms, Marcel Decker, New York, N.J. Y. , 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound of structure (I) and a pharmaceutically acceptable diluent, excipient, or carrier. In certain embodiments, the compounds described are administered as pharmaceutical compositions in which the compound of structure (I) is mixed with other active ingredients for combination therapy. All combinations of active agents described in the Combination Therapy section below and throughout this disclosure are included herein. In certain embodiments, pharmaceutical compositions comprise one or more compounds of structure (I).

A pharmaceutical composition, as used herein, includes other chemical components of a compound of structure (I) (carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients, etc.). In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, in practicing the methods of treatment or methods of use provided herein, a therapeutically effective amount of a compound of structure (I) provided herein is included in a pharmaceutical composition. It is administered to a mammal having a disease, disorder or condition to be treated. In certain embodiments, the mammal is human. In certain embodiments, a therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds described herein are used alone or in combination with one or more therapeutic agents as components of mixtures.

In one embodiment, one or more compounds of structure (I) are formulated in an aqueous solution. In certain embodiments, the aqueous solution is selected from physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer, by way of example only. In other embodiments, one or more compounds of structure (I) are formulated for transmucosal administration. In certain embodiments, transmucosal formulations include penetrants appropriate to the barrier to be permeated. In still other embodiments in which the compounds described herein are formulated for parenteral injection, suitable formulations include aqueous or non-aqueous solutions. In certain embodiments, such solutions comprise physiologically compatible buffers and/or excipients.

In another embodiment, the compounds described herein are formulated for oral administration. The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds described herein are formulated in oral dosage forms, which include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, Including elixirs, slurries, suspensions and the like.

In certain embodiments, pharmaceutical preparations for oral use are mixed with one or more solid excipients with one or more compounds described herein, and the resulting mixture is Obtained by processing a mixture of granules, optionally after grinding and, if necessary, addition of suitable adjuvants, to obtain tablets or dragee cores. Suitable excipients are, inter alia, sugars including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.); or others (such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate). In certain embodiments, disintegrants are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or salts thereof such as sodium alginate.

In one embodiment, dosage forms (such as dragee cores and tablets) are provided with one or more suitable coatings. In certain embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solution optionally contains further ingredients such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures, by way of example only. including. Dyes and/or pigments are also optionally added to the coating for identification purposes. In addition, dyes and/or pigments are used, as appropriate, to characterize different combinations of active compound doses.

In certain embodiments, a therapeutically effective amount of at least one compound described herein is formulated in other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain embodiments, push-fit capsules contain the active ingredients in admixture with one or more fillers. Fillers include, by way of example only, lactose, binders such as starch, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In other embodiments, soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers are added as required.

In other embodiments, a therapeutically effective amount of at least one compound described herein is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges or gels. In still other embodiments, the compounds described herein are formulated for parental injection (including formulations suitable for bolus injection or continuous infusion). In certain embodiments, formulations for injection are presented in unit dosage form (eg, in ampoules) or in multi-dose containers. Preservatives are added to injection formulations as needed. In still other embodiments, pharmaceutical compositions are formulated as suspensions, solutions, or emulsions in sterile oily or aqueous vehicles in a form suitable for parenteral injection. Parenteral injection preparations optionally contain formulating agents (such as suspending, stabilizing, and/or dispersing agents). In certain embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In further embodiments, suspensions of the active compounds (eg, compounds of structure (I)) are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides; or liposomes. In certain embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) before use.

In still other embodiments, compounds of structure (I) are administered topically. The compounds described herein are formulated into various topical compositions such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

In still other embodiments, the compounds of structure (I) are formulated for transdermal administration. In certain embodiments, transdermal formulations may be lipophilic emulsions or aqueous buffer solutions dissolved and/or dispersed in polymers or adhesives using transdermal delivery devices and transdermal delivery patches. In various embodiments, such patches are constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. In further embodiments, compounds of structure (I) are transdermally delivered using iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of compounds of structure (I). In certain embodiments, the rate of absorption is reduced through the use of rate-limiting membranes or entrapment of the compound within a polymer matrix or gel. In another embodiment, absorption enhancers are used to increase absorption. An absorption enhancer or carrier includes absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, in one embodiment, a transdermal device comprises a backing member, a reservoir containing the compound, optionally with a carrier, and an optional compound to deliver the compound to the skin of the host at a controlled and predetermined rate over an extended period of time. It is in the form of a bandage that includes a rate-limiting barrier and a means of securing the device to the skin.

In other embodiments, the compounds of structure (I) are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. Pharmaceutical compositions of any of the compounds of structure (I) use a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. It is conveniently delivered in the form of an aerosol spray provided from a pressurized pack or nebulizer. In certain embodiments, the unit dose of pressurized aerosol is determined by providing a valve to deliver a metered dose. In certain embodiments, by way of example only, capsules and cartridges such as gelatin containing a powder mix of the compound and a suitable powder base such as lactose or starch are formulated for use in an inhaler or insufflator.

In still other embodiments, compounds of structure (I) are used in rectal compositions (enemas, rectal gels, etc.) comprising conventional suppository bases (such as cocoa butter or other glycerides) and synthetic polymers (such as polyvinylpyrrolidone and PEG). , rectal foam, rectal aerosol, suppository, jelly suppository, or retention enema). For suppository forms of the composition, a low melting wax such as, but not limited to, a mixture of fatty acid glycerides optionally combined with cocoa butter is melted first.

In certain embodiments, pharmaceutical compositions are in any conventional manner using one or more physiologically acceptable carriers including excipients and adjuvants that facilitate processing of the active compounds. It has been formulated into a preparation that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers and excipients are used as appropriate. A pharmaceutical composition comprising a compound of structure (I) is prepared in a conventional manner, such as by conventional mixing, dissolving, granulating, dragee-making, wet-milling, emulsifying, encapsulating, entrapping, or compressing processes. ) to manufacture.

Pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one compound of structure (I) as described herein as an active ingredient. The active ingredient is in free acid or free base form or a pharmaceutically acceptable salt form. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds that have the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein include unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water and ethanol. The solvated forms of the compounds presented herein are also considered disclosed herein. Furthermore, the pharmaceutical composition may optionally contain other pharmaceuticals or pharmaceuticals, carriers, adjuvants (preservatives, stabilizers, wetting agents or emulsifiers, solubility enhancers, salts for adjusting osmotic pressure, buffering agents). , and/or other pharmaceutically beneficial substances).

Methods of preparing compositions containing the compounds described herein include one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semisolid, or liquid. formulating the compound using. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compounds are dissolved, emulsions containing the compounds, or solutions containing liposomes, micelles, or nanoparticles containing the compounds disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. Forms of the pharmaceutical compositions described herein include solutions or suspensions, solids suitable for solution or suspension in liquid prior to use, or emulsions. These compositions, if desired, also contain minor amounts of nontoxic, auxiliary substances such as wetting or emulsifying agents and pH buffering agents.

In some embodiments, pharmaceutical compositions comprising at least one compound of structure (I) are illustratively in the form of liquids in which the drug is in solution, suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the drug is in solution and a second portion of the drug is in suspension in a liquid matrix, in particulate form. Exists in form. In some embodiments, liquid compositions include gel formulations. In other embodiments, the liquid composition is aqueous.

In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulose polymers (eg, hydroxypropylmethylcellulose) and water-insoluble polymers such as crosslinked carboxyl-containing polymers. Certain pharmaceutical compositions described herein include, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, alginic acid. sodium, and a mucoadhesive polymer selected from dextran.

Useful pharmaceutical compositions also optionally contain a solubilizing agent to aid in the solubility of the compound of structure (I). The term "solubilizing agents" generally includes agents that form micellar or true solutions of drugs. Certain acceptable nonionic surfactants (eg, polysorbate 80) are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols (eg, polyethylene glycol 400), and glycol ethers. be.

In addition, useful pharmaceutical compositions optionally contain one or more pH adjusting or buffering agents (acids such as acetic, boric, citric, lactic, phosphoric, and hydrochloric; sodium hydroxide; , sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate, and ammonium chloride). include. Such acids, bases and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

In addition, useful compositions also optionally contain one or more salts in amounts necessary to bring the composition's osmolality to an acceptable range. Such salts include salts having sodium, potassium, or ammonium cations and chlorine, citrate, ascorbic, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

Other useful pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils (e.g. polyoxyethylene (60) hydrogenated castor oil); and polyoxyethylene alkyl ethers and alkylphenyl ethers (e.g. octoxynol 10, Octoxynol 40) is included.

Still other useful compositions optionally include one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose resealable containers are used where it is typical to include a preservative in the composition.

In another embodiment, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In a further embodiment, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds over a period of several weeks up to 100 days. Due to the chemical nature and biological stability of therapeutic reagents, additional protein stabilization strategies are used.

In certain embodiments, formulations described herein include one or more antioxidants, metal chelating agents, thiol-containing compounds, and/or other general stabilizers. Examples of such stabilizers include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v (c) about 0.1% to about 2% w/v monothioglycerol; (d) about 1 mM to about 10 mM EDTA; (e) about 0.01% to about 2% w/v ascorbic acid; (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v polysorbate 20, (h) arginine, (i) heparin, (j) ) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

In some embodiments, the concentration of one or more compounds provided in a pharmaceutical composition of the invention is 100%, 90%, w/w, w/v, or v/v. 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10% , 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0. 1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.01% 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.009% 0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or less than 0.0001%.

In some embodiments, the concentration of one or more compounds of the invention is 90%, 80%, 70%, 60%, 50%, w/w, w/v, or v/v, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14 .75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9 .25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.7
5%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4 %, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125% , 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0 greater than .0003%, 0.0002%, or 0.0001%.

In some embodiments, the concentration of one or more compounds of the invention is about 0.0001% to about 50%, about 0.001% w/w, w/v, or v/v. about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10%.

In some embodiments, the concentration of one or more compounds of the invention is about 0.001% to about 10%, about 0.01% w/w, w/v, or v/v. about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about It is in the range of 0.9%.

In some embodiments, the amount of one or more compounds of the invention is , 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0 .9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g , 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0 .01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g , 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of one or more compounds of the invention is .0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g , 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0 .035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g , 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g,
, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1. 5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, Or over 10g.

In some embodiments, the amount of one or more compounds of the invention is 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g , 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

Kits/Articles of Manufacture Kits and articles of manufacture are also provided for use in the therapeutic applications described herein. In some embodiments, such kits include carriers, packages, or containers that contain one or more containers, such as vials and tubes, each container being used in the methods described herein. are compartmentalized to contain individual elements (including one of the individual elements that should be Suitable containers include, for example, bottles, vials, syringes, and test tubes. Containers are formed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein include packaging materials. Packaging materials used in packaging pharmaceutical products include, for example, those found in US Pat. Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging suitable for the formulation selected and the intended mode of administration and treatment. Materials include, but are not limited to. For example, the container(s) contain one or more of the compounds described herein, optionally in composition or in combination with another agent disclosed herein. The container(s) optionally have a sterile access port (eg, the container is an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally include a compound with an identifying description or label or instructions for its use in the methods described herein.

For example, kits typically include one or more additional containers, each containing one or more of the commercially and user-desirable uses of the compounds described herein. of different materials (reagents and/or devices optionally in concentrated form). Non-limiting examples of such materials include buffers, diluents, filters, needles, syringes; labels on carriers, packages, containers, vials, and/or tubes listing contents and/or instructions for use; Includes, but is not limited to, a package insert containing directions for use. A set of instructions will also typically be included. A label is optionally on or with the container. For example, when letters, numbers, or other symbols forming a label are applied, molded, or etched onto the container itself, the label resides on the container and within a reservoir or carrier that also holds the container. For example, if the label is present as a package insert, the label is present with the container. Additionally, labels are used to indicate that the contents are to be used for a specific therapeutic application. Further, the label indicates use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack includes, for example, metal or plastic foil (such as a blister pack). Alternatively, the pack or dispenser device is accompanied by instructions for administration. Alternatively, the pack or dispenser is accompanied by a notice relating to the container in the form directed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, and this notice is a person or entity authorized by the governmental agency. It reflects the form of drug for administration to animals. Such notice may, for example:
A prescription drug label or approved product insert approved by the U.S. Food and Drug Administration. In some embodiments, compositions comprising a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in a suitable container, and labeled for treatment of an indicated condition.

Methods Embodiments of the present invention provide a method of inhibiting RAS-mediated cell signaling comprising contacting a cell with an effective amount of one or more compounds disclosed herein. do. Inhibition of RAS-mediated signaling can be assessed and demonstrated by a wide variety of methods known in the art. Non-limiting examples include showing: (a) decreased GTPase activity of RAS; (b) decreased GTP binding affinity or increased GDP binding affinity; (c) K of GTP (d) decreased levels of signaling molecules downstream of the RAS pathway, such as decreased levels of pMEK; and/or (e) downstream signaling molecules, including Raf, reduced binding of the RAS complex to (but not limited to). Kits and commercially available assays are available for one or more of the above determinations.

Embodiments also treat medical conditions, including but not limited to conditions associated with G12C KRAS, HRAS, or NRAS mutations, G12C HRAS mutations and/or G12C NRAS mutations (e.g., cancer) A method of using a compound or pharmaceutical composition of the invention for is provided.

In some embodiments, a method of treating cancer is provided, comprising administering to a subject in need of treatment for cancer an effective amount of the aforementioned pharmaceutical composition comprising a compound of structure (I) administering any of the substances. In some embodiments, the cancer is mediated by a KRAS, HRAS, or NRAS G12C mutation. In other embodiments, the cancer is pancreatic cancer, colon cancer, MYH-associated polyposis, colorectal cancer, or lung cancer.

In some embodiments, the invention provides a method of treating a disorder in a subject in need of treatment of the disorder comprising determining whether the subject has a KRAS, HRAS, or NRAS G12C mutation, If a subject is determined to have a KRAS, HRAS, or NRAS G12C mutation, a therapeutically effective dose of at least one compound of structure (I), or a pharmaceutically acceptable salt, ester, prodrug, or A method is provided comprising administering a variant, solvate, hydrate, or derivative to a subject.

The disclosed compounds potently inhibit anchorage-independent cell growth and thus have the potential to inhibit tumor metastasis. Accordingly, in another embodiment, the present disclosure provides a method of inhibiting tumor metastasis comprising a pharmaceutical composition comprising an effective amount of any compound disclosed herein and a pharmaceutically acceptable carrier. Methods are provided comprising administering to a subject in need of inhibiting tumor metastasis.

KRAS, HRAS, or NRAS G12C mutations have also been identified in hematologic malignancies, such as cancers that affect the blood, bone marrow, and/or lymph nodes. Accordingly, certain embodiments relate to administration of disclosed compounds (eg, in the form of pharmaceutical compositions) to patients in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, compounds of the present disclosure can be used to treat acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML). ), acute monocytic leukemia (AMoL), and/or other leukemias. In other embodiments, the compounds are useful for treating lymphoma, such as Hodgkin's lymphoma or all subtypes of non-Hodgkin's lymphoma.

determining whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation; evaluating the nucleotide sequence encoding the KRAS, HRAS, or NRAS protein; evaluating the amino acid sequence of the KRAS, HRAS, or NRAS protein; or by evaluating the characteristics of putative KRAS, HRAS, or NRAS mutant proteins. Wild-type human KRAS, HRAS, or NRAS sequences are known in the art (eg, Accession No. NP203524).

Methods for detecting KRAS, HRAS, or NRAS nucleotide sequence mutations are known to those of skill in the art. These methods include polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single stranded DNA conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR array determination, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and Including but not limited to microarray analysis. In some embodiments, samples are evaluated for KRAS, HRAS, or NRAS mutations in G12C by real-time PCR. Real-time PCR uses fluorescent probes specific for the G12C mutation of KRAS, HRAS, or NRAS. If a mutation is present, the probe will bind and fluorescence will be detected. In some embodiments, the KRAS, HRAS, or NRAS G12C mutation is identified using direct sequencing of a specific region (e.g., exon 2 and/or exon 3) in the KRAS, HRAS, or NRAS gene. to identify. This technique identifies all possible mutations in the sequenced region.

Methods of detecting mutations in KRAS, HRAS, or NRAS proteins are known to those of skill in the art. These methods include detection of KRAS, HRAS, or NRAS variants using binding agents (e.g., antibodies) specific for the variant protein, protein electrophoresis, and Western blotting, and direct peptide sequencing. but not limited to these.

Methods for determining whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation can use a variety of samples. In some embodiments, a sample is taken from a subject with a tumor or cancer. In some embodiments, a sample is taken from a subject with cancer or tumor. In some embodiments, the sample is a fresh tumor/cancer sample. In some embodiments, the sample is a frozen tumor/cancer sample. In some embodiments, the sample is a formalin-fixed, paraffin-embedded sample. In some embodiments, samples are processed into cell lysates. In some embodiments, samples are processed into DNA or RNA.

Embodiments of the invention also include administering to a mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. , relates to methods of treating hyperproliferative disorders in mammals. In some embodiments, the method relates to the treatment of cancers such as: acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal Cancer, appendiceal cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, bar Kit lymphoma, carcinoid tumor, atypical teratoid tumor, fetal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), a chronic myleoproliferative disorder
disorder), colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal intraepithelial carcinoma (DCIS), embryonal tumor, CNS cancer, endometrial cancer, ependymoma, esophagus Cancer, sensory neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal tract Stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, renal cancer, laryngeal cancer, oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic cervical cancer of unknown primary Partial squamous cell carcinoma, median duct carcinoma, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplasia/myeloproliferation multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, para ganglionoma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, migration Cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer (stomach cancer), small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer , thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, rare cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral induced cancer. In some embodiments, the method treats a noncancerous hyperproliferative disorder, such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)). Regarding treatment.

In certain specific embodiments, the invention provides a method of treating lung cancer, comprising administering an effective amount of any of the above compounds (or a pharmaceutical composition comprising the above compounds) to a subject in need of treatment for lung cancer. to a method comprising the step of In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC) (eg, adenocarcinoma, lung squamous cell carcinoma, or large cell lung cancer). In other embodiments, the lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, adenocarcinoma, carcinoid tumor, and undifferentiated cancer.

A subject that can be treated with a compound of the invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate, or derivative of said compound according to a method of the invention. The body includes, for example, subjects who have been diagnosed with: acute myeloid leukemia, acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer , bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoid tumor, fetal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), fetal tumor , CNS cancer, endometrial cancer, ependymoma, esophageal cancer, sensory neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, ocular cancer, fibrous histiocytes of bone tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, renal cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular intraepithelial cancer (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma of the neck of unknown primary, median duct carcinoma, mouth cancer, multiple endocrine tumor syndrome, multiple myeloma/plasma cell neoplasm, fungi myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity carcinoma and accessory nasal cavity cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip cancer and oral cancer
cavity cancer), oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleural lung Blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach cancer (gastric cancer), small cancer Cell lung cancer, small bowel cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, childhood Rare cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer. In some embodiments, subjects treated with a compound of the invention have a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia). Included are subjects diagnosed with hypertrophy (BPH), etc.).

Embodiments of the invention further provide methods of modulating G12C mutant KRAS, HRAS, or NRAS protein activity by contacting said protein with an effective amount of a compound of the invention. Modulation can be inhibition or activation of protein activity. In some embodiments, the invention provides methods of inhibiting protein activity by contacting a G12C mutant KRAS, HRAS, or NRAS protein in solution with an effective amount of a compound of the invention. In some embodiments, the invention provides methods of inhibiting G12C mutant KRAS, HRAS, or NRAS protein activity by contacting with a cell, tissue, organ that expresses the protein of interest. In some embodiments, the present invention provides for the detection of protein activity in a subject (including, but not limited to, rodents and mammals (e.g., humans)) by administering an effective amount of a compound of the present invention to the subject. provided is a method of inhibiting by administering to In some embodiments, the adjustment rate is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percent inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the present invention provides the activity of KRAS, HRAS, or NRAS G12C in a cell, wherein said cell is treated with an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in said cell. A method of inhibiting by contacting with a compound of the invention is provided. In some embodiments, the present invention provides an amount of KRAS, HRAS, or NRAS G12C in a tissue sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in said tissue. A method of inhibiting by contacting with a compound of the invention is provided. In some embodiments, the present invention provides the activity of KRAS, HRAS, or NRAS G12C in an organism by treating said organism with an amount sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in said organism. A method of inhibiting by contacting with a compound of the invention is provided. In some embodiments, the present invention provides for the activity of KRAS, HRAS, or NRAS G12C in an animal by treating said animal with an amount of KRAS, HRAS, or NRAS G12C sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in said animal. A method of inhibiting by contacting with a compound of the invention is provided. In some embodiments, the invention provides an activity of KRAS, HRAS, or NRAS G12C in a mammal sufficient to inhibit the activity of KRAS, HRAS, or NRAS G12C in said mammal. A method of inhibiting by contacting with an amount of a compound of the invention is provided. In some embodiments, the invention provides for KRAS, HRAS, or NRAS in humans.
A method is provided for inhibiting the activity of G12C by contacting said human with a compound of the invention in an amount sufficient to inhibit the activity of KRAS, HRAS or NRAS G12C in said human. In other embodiments, the invention provides KRAS, HRAS, or NRAS
Methods are provided for treating diseases mediated by the activity of G12C in a subject in need of such treatment.

Other embodiments combine agents known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes, with compounds of the invention, or pharmaceutically acceptable salts thereof, Methods are provided for combination therapy using the esters, prodrugs, solvates, tautomers, hydrates, or derivatives in combination. In one aspect, such treatment includes combining one or more compounds of the invention with chemotherapeutic agents, therapeutic antibodies, and radiation treatment to obtain a synergistic or additive therapeutic effect. include, but are not limited to:

Numerous chemotherapeutic agents are now known in the art and can be used in combination with the compounds of the present invention. In some embodiments, the chemotherapeutic agent is a mitotic inhibitor, an alkylating agent, an antimetabolite, an intercalating antibiotic, a growth factor inhibitor, a cell cycle inhibitor, an enzyme, a topoisomerase inhibitor, a biological response modifier, an anti Selected from the group consisting of hormones, angiogenesis inhibitors, and antiandrogens.

Non-limiting examples include chemotherapeutic agents, cytotoxic agents, non-peptide small molecules (Gleevec® (imatinib mesylate), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin), as well as numerous chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (Cytoxan®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines (such as benzodopa, carbocone, metledopa, and uredopa); ethyleneimines and methylmelamines (including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamines); nitro Genmustard (chlorambucil, chlornafadine, colophosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobuenbiquin, phenesterin, prednimustine, trophosphamide, uracil mustard, etc.); nitrosoureas (carmustine, chlorozotocin, fotemustine) , lomustine, nimustine, ranimustine, etc.); ), chromomycin, dactinomycin, daunorubicin, detrubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, ethorubicin, idarubicin, marceromycin, mitomycin, mycophenolic acid, nogaramycin, olibomycin, peplomycin, poto philomycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin, etc.); antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); , pteropterin, trimetrexate, etc.); purine analogs (fludarabine, 6-mercaptopurine, thiamipurine, thioguanine, etc.); pyrimidine analogs (antcitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine) etc.), androgens (carsterone, dolo mostanolone propionate, epithiostanol, mepitiostane, testolactone, etc.); anti-adrenal agents (aminoglutethimide, mitotane, trilostane, etc.); folic acid supplements (floric acid, etc.); bisantrene; edatraxate; defofamine; demecolcine; diazicon; elfomitin;
lonidamine; mitoguazone; mitoxantrone; mopidamole; nitracrine; pentostatin; vindesine; dacarbazine; mannomustine; mitobronitol; mitractol; ), Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (Taxotere™, Rhone-Poulenc Rorer, Antony, France)); retinoic acid; esperamicin; capecitabine; are acceptable salts, acids, or derivatives thereof. Suitable chemotherapeutic cell regulators include antihormonal agents (antiestrogenic agents such as tamoxifen (Nolvadex™), raloxifene, aromatase inhibitor 4(5)-imidazole, which act to modulate or inhibit hormone action on tumors). , 4-hydroxy tamoxifen, trioxyfen, keoxifene, LY 117018, onapristone, and toremifene (Fairstone)); and antiandrogens (such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin)); chlorambucil; mercaptopurine; methotrexate; platinum analogues (such as cisplatin and carboplatin); vinblastine; platinum; etoposide (VP-16); ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO). Optionally, the compounds or pharmaceutical compositions of the present invention can be combined with commonly prescribed anticancer drugs (Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol ( Registered Trademark), Arimidex®, Taxotere®, ABVD, AVICINE, Avagobomab, Acridinecarboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, Alfaladin, Arbocidib, 3-aminopyridine -2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agents, anti-tumorigenic herbs, apazicon, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, viricodar, brostalysin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), caliculin, cell cycle non-specific antineoplastic agents, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, feruginol, forodecin, phosfest rol, ICE chemotherapy regimen, IT-101, imexone, imiquimod, indolocarbazole, irofulvene, ranicuidar, larotaxel, lenalidomide, lucanthone, rutotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone , proteasome inhibitors, rebecamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, talychidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl) amine, troxacitabine, uramustine, bajimezan, vinflunine, ZD6126, or zosuquidar).

Embodiments further relate to methods of using compounds or pharmaceutical compositions provided herein in combination with radiation therapy for inhibition of abnormal cell growth or treatment of hyperproliferative disorders in mammals. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. Administration of the compounds of the invention in this combination therapy can be determined as described herein.

Radiation therapy can be administered in one or a combination of several methods (external beam radiation therapy, internal radiation therapy, interstitial radiation therapy, stereotactic radiation therapy, total body radiation therapy, radiation therapy and continuous or temporary intra- tissue radiation therapy). including but not limited to brachytherapy). The term "brachytherapy," as used herein, refers to radiation therapy delivered by spatially restricted radioactive material inserted at or near the diseased site of a tumor or other proliferating tissue in the body. say. This term includes radioactive Isotopes) are intended to include, but are not limited to. Radiation sources suitable for use as cell conditioning agents in the present invention include both solids and liquids. As non-limiting examples, the radiation source can be a radionuclide (such as I-125, I-131, Yb-169, Ir-192 as solid-state sources, I-125 as solid-state sources), or emit photons. other radionuclides, beta particles, gamma rays, or other therapeutic radiation. The radioactive material can also be a fluid made from any radionuclide solution (e.g., a solution of 1-125 or 1-131), or the radioactive fluid can be a solid radionuclide (Au-198, Y-90, etc.). It can be produced using a slurry of a suitable fluid containing small particles. Additionally, radionuclides can be incorporated into gels or radioactive microspheres.

Without being bound by any theory, the compounds of the invention may render abnormal cells more susceptible to treatment with irradiation for the purpose of killing and/or inhibiting growth of such cells. Accordingly, the present invention further provides a method of increasing the susceptibility of abnormal cells in a mammal to treatment using irradiation comprising a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, A method comprising administering a solvate, hydrate, or derivative to a mammal in an amount effective to increase the susceptibility of abnormal cells to treatment using irradiation. The amount of compound, salt, or solvate in the method can be determined according to any means of ascertaining an effective amount of such compound described herein.

A compound or pharmaceutical composition of the invention in combination with an amount of one or more substances selected from antiangiogenic agents, signaling inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors can be used.

Anti-angiogenic agents, such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, can be used in the present invention described herein. It can be used in conjunction with the compounds and pharmaceutical compositions of the invention. Antiangiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include Celebrex™ (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are WO 96/33172 (published Oct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European Patent Application No. 97304971.1 (July 1997). 8 June 1998), European Patent Application No. 99308617.2 (filed 29 October 1999), WO 98/07697 (published 26 February 1998), WO 98/03516 (published 29 January 1998) ), WO98/34918 (published August 13, 1998), WO98/34915 (published August 13, 1998), WO98/33768 (published August 6, 1998), WO98/30566 (1998 European Patent Publication No. 606,046 (published July 13, 1994), European Patent Publication No. 931,788 (published July 28, 1999), WO 90/05719 (1990). Published on May 31, 2019), WO
99/52910 (published Oct. 21, 1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (published Jun. 17, 1999), PCT International Application No. PCT/IB98/ 01113 (filed July 21, 1998), European Patent Application No. 99302232.1 (filed March 25, 1999), UK Patent Application No. 9912961.1 (filed June 3, 1999), United States provisional Patent Application No. 60/148,464 (filed Aug. 12, 1999); U.S. Patent No. 5,863,949 (issued Jan. 26, 1999); published Jan. 19), and European Patent Publication No. 780,386 (published Jun. 25, 1997), all of which are incorporated herein by reference. Preferred MMP-2 inhibitors and MMP-9 inhibitors are those that have little or no MMP-1 inhibitory activity. other matrix-metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-ll, MMP-12, and More preferred are inhibitors that selectively inhibit MMP-2 and/or AMP-9 compared to MMP-13). Some specific examples of MMP inhibitors useful in the present invention are AG-3340, RO32-3555, and RS13-0830.

Autophagy inhibitors include chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, protein phosphatase type 2A or Examples include, but are not limited to, autophagy-inhibiting algal toxins that inhibit type 1, analogs of cAMP, and drugs that elevate cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, antisense or siRNA that inhibit expression of proteins, including but not limited to ATG5 (which is involved in autophagy), can also be used.

Embodiments also include an amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, tautomer, hydrate, or derivative thereof, or isotopically labeled The present invention relates to methods and pharmaceutical compositions for the treatment of cardiovascular disease in mammals comprising a derivative of the present invention and an amount of one or more therapeutic agents for the treatment of cardiovascular disease.

Exemplary agents for use in cardiovascular disease include antithrombotic agents (such as prostacyclins and salicylates), thrombolytic agents (such as streptokinase, urokinase, tissue plasminogen activator (TPA), and anisoylated plasminogen- streptokinase activator complex (APSAC)), antiplatelet agents (e.g. acetyl-salicylic acid (ASA) and clopidrogel), vasodilators (e.g. nitrates), calcium channel blockers, antiproliferative agents (e.g. colchicine and alkyl intercalating agents), intercalating agents, growth regulators (such as interleukins, transforming growth factor-β, and platelet-derived growth factor congeners, monoclonal antibodies directed against growth factors), anti-inflammatory agents (steroidal and non-steroidal ), and other agents that can modulate vascular tone, function, arteriosclerosis, and the healing response to post-interventional vascular or organ injury. Antibiotics can also be included in combinations or coatings included in the present invention. Additionally, coatings can be used to deliver therapeutic agents locally within the vessel wall. By incorporating an active agent into a swellable polymer, the active agent is released upon swelling of the polymer.

In some embodiments, the compounds described herein are formulated or administered in conjunction with liquid or solid tissue barriers, also known as lubricants. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, Seprafilm, Interseed, and hyaluronic acid.

In some embodiments, pharmaceutical agents administered in conjunction with compounds described herein include any suitable drug that is usefully delivered by inhalation, such as analgesics (e.g., codeine, dihydromorphine, ergotamine, fentanyl, or morphine); angina preparations (eg, diltiazem); anti-allergic drugs (eg, cromoglycate, ketotifen, or nedocromil); anti-infectives (eg, cephalosporins, penicillins, streptomycin, sulfonamides) , tetracycline, or pentamidine); antihistamines (e.g., metapyrylene; anti-inflammatory agents (e.g., beclomethasone, flunisolide, budesonide, tipredan, triamcinolone acetonide, or fluticasone); antitussives (e.g., noscapine); , ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, limiterol, salbutamol, salmeterol, terbutaline, isoetaline, tulobuterol, orciprenaline, or (−)-4-amino-3, 5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol); diuretics (eg amiloride); anticholinergics (eg ipratropium, atropine) hormones (e.g., cortisone, hydrocortisone, or prednisolone); xanthines (e.g., aminophylline, choline theophylinate, lysine theophylinate, or theophylline); and therapeutic proteins and peptides (e.g., insulin or glucagon)), where appropriate, in salt form (e.g., as an alkali metal or amine salt or as an acid addition salt) to optimize drug activity and/or stability. , or as esters (eg lower alkyl esters) or as solvates (eg hydrates).

Other exemplary therapeutic agents useful in combination therapy include the radiation therapy agents described above, hormone antagonists, hormones and their releasing factors, thyroid and antithyroid agents, estrogens and progestins, androgens, adrenocorticotropic hormones; Steroids and their synthetic analogues; inhibitors of adrenocortical hormone synthesis and action, insulin, oral hypoglycemic agents, and pharmacological actions of the endocrine pancreas, agents affecting mineralization and bone turnover: calcium, phosphate, parathyroid hormone , vitamin D, calcitonin, vitamins (such as water-soluble vitamins, vitamin B complex, ascorbic acid, fat-soluble vitamins, vitamins A, K, and E), growth factors, cytokines, chemokines, muscarinic receptor agonists and antagonists; anticholinesterases agents that act at the neuromuscular junction and/or autonomic ganglia; catecholamines, sympathomimetic agents, and agonists or antagonists of adrenergic receptors; and 5-hydroxytryptamine (5-HT, serotonin) receptors. include, but are not limited to, agonists and antagonists of

Therapeutic agents include drugs for pain and inflammation (histamine and histamine antagonists, brandykinin and brandykinin antagonists, 5-hydroxytryptamine (serotonin), etc.), by biotransformation of selective hydrolysis products of membrane phospholipids. Lipid substances produced, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, non-steroidal anti-inflammatory agents, analgesics-antipyretics, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective for inducible cyclooxygenase Inhibitors, selective inhibitors of inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, beta-adrenergic Sexual agonists, ipratropium, glucocorticoids, methylxanthines, sodium channel blockers, opioid receptor agonists, calcium channel blockers, membrane stabilizers, and leukotriene inhibitors may also be included.

Additional therapeutic agents contemplated herein include diuretics, vasopressin, agents affecting water retention within the kidney, rennin, angiotensin, agents useful in treating myocardial ischemia, antihypertensive agents, angiotensin converting enzyme. Included are inhibitors, beta-adrenergic receptor antagonists, agents for treating hypercholesterolemia, and agents for treating dyslipidemia.

Other therapeutic agents contemplated include drugs used to control gastric acidity, drugs for the treatment of peptic ulcers, drugs for the treatment of gastroesophageal reflux disease, prokinetic agents, antiemetics, drugs used for irritable bowel syndrome, drugs used for diarrhea, drugs used for constipation, drugs used for inflammatory bowel disease, drugs used for bile duct disease, Includes drugs used for pancreatic disease. Therapeutic agents used to treat protozoan infections, drugs used to treat malaria, amebiasis, giardiasis, trichomoniasis, trypasonomatosis, and/or leishmaniasis, and/or helminthiasis drugs used in chemotherapy for Other therapeutic agents include antibacterial agents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, and agents for urinary tract infections, penicillins, cephalosporins, etc., beta-lactam antibiotics, aminoglycosides, Included are protein synthesis inhibitors, drugs used in chemotherapy for tuberculosis, Mycobacterium avium complex disease, and leprosy, antifungals, antivirals (including nonretrovirals and antiretrovirals).

Examples of therapeutic antibodies that can be combined with the compounds of the invention include anti-receptor tyrosine kinase antibodies (cetuximab, panitumumab, trastuzumab), anti-CD20 antibodies (rituximab, tositumomab), and other antibodies (alemtuzumab, bevacizumab, and gemtuzumab, etc.).

In addition, therapeutic agents used for immunomodulation (such as immunomodulatory agents, immunosuppressive agents, tolerogens, and immunostimulatory agents) are contemplated in the methods herein. In addition, therapeutic agents acting on the blood and blood-forming organs, hematopoietic agents, growth factors, minerals and vitamins, anticoagulants, thrombolytic agents and antiplatelet agents.

For the treatment of renal cancer, compounds of the invention can be combined with sorafenib and/or Avastin. For the treatment of endometrial disorders, the compounds of the invention can be combined with doxorubicin, taxotere (Taxol), and/or cisplatin (carboplatin). For the treatment of ovarian cancer, the compounds of the invention can be combined with cisplatin (carboplatin), taxotere, doxorubicin, topotecan, and/or tamoxifen. Combining a compound of the invention with Taxotere (Taxol), Gemcitabine (Capecitabine), Tamoxifen, Letrozole, Tarceva, Lapatinib, PD0325901, Avastin, Herceptin, OSI-906, and/or OSI-930 for the treatment of breast cancer can be done. For the treatment of lung cancer, the compounds of the invention can be combined with Taxotere (Taxol), Gemcitabine, Cisplatin, Pemetrexed, Tarceva, PD0325901, and/or Avastin.

In other embodiments, agents useful in the methods for combination therapy with one or more compounds of structure (I) include erlotinib, afatinib, Iressa, GDC0941, MLN1117, BYL719 (alpelisib), BKM120 (ブパルリシブ（Ｂｕｐａｒｌｉｓｉｂ））、ＣＹＴ３８７、ＧＬＰＧ０６３４、バリシチニブ、レスタウルチニブ、モメロチニブ、パクリチニブ、ルキソリチニブ、ＴＧ１０１３４８、クリゾチニブ、チバンチニブ、ＡＭＧ３３７、カボザンチニブ、フォレチニブ、オナルツズマブ、ＮＶＰ－ＡＥＷ５４１、ダサチニブ、ポナチニブ、サラカチニブ、ボスチニブ、トラメチニブ、セルメチニブ、コビメチニブ、ＰＤ０３２５９０１、ＲＯ５１２６７６６、アクシチニブ、ベバシズマブ、ボスチニブ（Ｂｏｓｔｕｔｉｎｉｂ）、セツキシマブ、クリゾチニブ、ホスタマチニブ、ゲフィチニブ、イマチニブ、ラパチニブ、レンバチニブ、イブルチニブ、ニロチニブ、パニツムマブ、パゾパニブ、ペガプタニブ、ラニビズマブ、ルキソリチニブ、ソラフェニブ、スニチニブ、ＳＵ６６５６、トラスツズマブ, tofacitinib, vandetanib, vemurafenib, irinotecan, taxol, docetaxel, rapamycin, or MLN0128.

Additional therapeutic agents that can be combined with the compounds of the present invention are described in Goodman and Gilman's "The Pharmacological Basis of
Therapeutics" Tenth Edition edited by Hardman, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein by reference in their entireties.

Compounds described herein can be used in combination with the agents disclosed herein or other appropriate agents, depending on the condition to be treated. Therefore, in some embodiments, one or more compounds of the invention are co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered either simultaneously or separately with the second agent. This combined administration can include co-administration of the two agents in the same dosage form, co-administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the above agents can be formulated together in the same dosage form and administered at the same time. Alternatively, a compound of the invention and any of the above agents in separate formulations can be co-administered. In another alternative, any of the above agents may be administered immediately following administration of the compound of the invention, or vice versa. In some embodiments of the separate administration protocol, the compound of the invention and any of the above agents are administered separated by minutes, hours, or days.

The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It should be understood that the scope of this invention is in no way limited to the scope of the examples and preparations below. In the following examples and throughout the specification and claims, molecules with a single stereocenter are present as racemic mixtures unless otherwise indicated. Molecules with two or more stereocenters exist as racemic mixtures of diastereomers unless otherwise indicated. Single enantiomers/diastereomers can be obtained by methods known to those skilled in the art.

The following examples are provided for illustrative purposes. Exemplary compounds of structure (I) were prepared according to procedures analogous to the specific examples below. Other methods of preparing compounds of structure (I) are known in the art or can be derived by one skilled in the art.

Example 1
Synthesis of 6-(1-acryloylazetidin-3-yl)-2-(3-hydroxynaphthalen-1-yl)-3,4-dihydroisoquinolin-1(2H)-one

Example 2
Synthesis of 5-(1-acryloylazetidin-3-yl)-2-(5-methyl-1H-indazol-4-yl)isoindolin-1-one

Example 3
Compound Biochemical Assays Test compounds were prepared as 10 mM stock solutions in DMSO (Fisher Catalog No. BP-231-100). KRAS G12C 1-169 (his-tagged protein, GDP loaded) was diluted to 2 μM or 0.5 μM in buffer (20 mM Hepes, 150 mM NaCl, 1 mM MgCl ₂ ). Compounds were tested for activity as follows.

Compounds were diluted in DMSO to 50× final test concentrations in 96-well storage plates. Compound stock solutions were vortexed prior to use and carefully observed for any signs of precipitation. Dilutions were made as follows.
• Compounds were diluted to 5000 μM (5 μL of 10 mM compound stock + 5 μL of DMSO) for a final compound concentration of 100 μM and mixed well by pipetting.
• Compounds were diluted to 1500 μM (3 μL 10 mM compound stock + 17 μL DMSO) for a final compound concentration of 30 μM and mixed well by pipetting.
• Compounds were diluted to 500 μM (2 μL of 10 mM compound stock + 38 μL of DMSO) for a final compound concentration of 10 μM and mixed well by pipetting.

49 μL of protein stock solution was added to each well of a 96-well PCR plate (Fisher catalog number 1423027). 1 μl of 50× diluted compound was added to appropriate wells in the PCR plate using a 12-channel pipettor. Reactions were carefully and thoroughly mixed by pipetting up and down using a 200 μL multichannel pipettor. Plates were well sealed with aluminum plate seals and stored in a drawer at room temperature for 10 minutes, 30 minutes, 2 hours, or 24 hours. 5 μL of 2% formic acid (Fisher Catalog No. A117) in deionized H ₂ O was then added to each well and mixed using a pipette. Plates were then resealed with aluminum seals and stored on dry ice until analysis as described below.

The assay was analyzed by mass spectrometry according to one of the following two procedures.

RapidFire/TOF Assay:
The MS instrument is set to positive polarity, 2 GHz resolution, and low mass (1700) mode and allowed to equilibrate for 30 minutes. The instrument is then calibrated, switched to acquisition mode, and the appropriate method loaded.

After an additional 30 minutes of equilibration time, run a blank batch (ie, buffer) to ensure that the instrument is working properly. Samples are thawed at 37°C for 10 minutes, centrifuged briefly, and transferred to the benchtop. Wells A1 and H12 are spiked with 1 μL of 500 μM internal standard peptide and the plate is centrifuged at 2000×g for 5 minutes. The method is then performed and the mass of each well recorded.

Paste the mass of each well (integrated data desired) into the plate map and export from analysis. Also export the mass of the internal standard. Data at 50 ppm are extracted for charge state +19 and the identity of well A1 is assigned and integrated using the internal standard spike. Export the peak data as a TOF list and repeat the above process for charge states +20, 21, 22, 23, 24, and 25 respectively.

Q-Exactive Assay:
Masses and peak intensities of the KRAS G12C protein species were measured on a Dionex coupled to a Q Exactive Plus mass spectrometer (Thermo Scientific).
Measurements were made using an RSLC nanosystem (Thermo Scientific).

20 mL of each sample was prepared using 20% solvent A (0.1% formic acid in _H2O ) and 80% solvent B (0.1% formic acid in acetonitrile) at 40 °C at a flow rate of 600 ^µL / _min . Loaded onto a maintained Aeris™ 3.6 μm WIDEPORE C4 200 Å, LC Column 50×2.1 mm column. Liquid chromatography conditions were 20% solvent B for 1 minute, 20%-60% solvent B for 1.5 minutes, 60%-90% solvent for 0.5 minutes, 90% solvent B for 0.2 minutes, 0 90% to 20% Solvent B for .2 minutes, followed by 1.6 minutes of equilibration followed by sample injection. The flow rate was maintained at 600 ^μL / _min throughout the analysis of samples.

The mass spectrometer was operated in profile mode with a resolution of 17500, 5 microscans using a maximum injection time of 50 ms and an AGC target of 1×10 ⁶ , recording the full mass range from 800 to 1850 m/z. . The HCD trapping gas was optimized for maximum sensitivity to intact proteins. The method of ionization was electrospray ionization using a spray voltage of 4 kV, sheath gas flow set at 50 AU, auxiliary gas flow set at 10 AU and sweep gas flow set at 1 AU. The capillary ion transfer temperature was 320° C. and the S-lens RF level was set at 50 volts. For quantitative deconvolution of the charge envelope of each protein species in the sample, the Protein Deconvolution software (Thermo Scientific) was used to determine the mass and intensity of each parent species (modified or unmodified protein). The percent modification was calculated based on the deconvoluted peak intensities.
Other in vitro analyzes are as follows.

Inhibition of cell growth:
The ability of compounds of the invention to inhibit RAS-mediated cell growth is evaluated and demonstrated as follows. Cells expressing wild-type RAS or mutant RAS are plated at a density of 5,000 cells/well in white clear-bottom 96-well plates. Cells are allowed to attach for approximately 2 hours after plating, after which compounds disclosed herein are added. After a period of time (e.g., after 24 hours, 48 hours, or 72 hours of cell growth), cell proliferation is measured for total ATP content using Cell Titer Glo reagent (Promega) according to the manufacturer's instructions. determined by The proliferation _EC50 is determined by analysis of an 8-point compound dose response decreasing in half-log intervals from 100 μM.

Inhibition of RAS-mediated signaling:
The ability of compounds disclosed herein to inhibit RAS-mediated signaling is evaluated and demonstrated as follows. Cells expressing wild-type RAS or mutant RAS (such as G12C, G12V, or G12A) are treated with or without compounds of the invention (control cells). Inhibition of RAS signaling by one or more compounds of the invention, phosphorylated MEK, phosphorylated ERK, phosphorylation in cells treated with one or more compounds of the invention compared to control cells Demonstrated by steady state levels of RSK and/or decreased Raf binding.

＋は、最大５％の結合活性を示す
＋＋は、５％～５０％の結合活性を示す
＋＋＋は、５０％超の結合活性を示す Compounds 1 and 2 were prepared and tested according to the procedures described above. After a 30 minute incubation period, each of these compounds covalently bound to KRAS G12C at a maximum of 5%. Other representative compounds of Table 1 were tested according to the methods described above and found to covalently bind KRAS G12C to the extent shown in Table 2 after a 30 minute incubation period.

+ indicates binding activity up to 5% ++ indicates binding activity between 5% and 50% +++ indicates binding activity greater than 50%

All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent literature mentioned herein and in attached application data sheets are by reference and not inconsistent with this specification in their entirety. incorporated herein to some extent.

US Provisional Application No. 62/450,953 (filed Jan. 26, 2017) is hereby incorporated by reference in its entirety.

From the foregoing, it will be appreciated that while specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. . Accordingly, the invention is not limited except as by the appended claims.

According to preferred embodiments of the present invention, for example, the following are provided.
(Section 1)
Structure (I) below:

[In the formula,
A is -LR ¹ and R ^2a , R ^2b and R ^2c 5- or 6-membered nitrogen-containing heterocyclyl or heteroaryl optionally substituted with 1, 2 or 3 additional substituents selected from the group consisting of;
B is C or N;
R. ^a , R ^b and R ^c is independently at each occurrence H, amino, cyano, halo, hydroxyl, C ₁ ～C ₆ alkyl, C ₁ ～C ₆ alkylamino, C ₁ ～C ₆ haloalkyl, C ₁ ～C ₆ Alkoxy, C ₁ ～C ₆ haloalkoxy; C ₃ ～C ₈ cycloalkyl, heterocyclylalkyl, C ₁ ～C ₆ alkynyl, C ₁ ～C ₆ alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
R. ¹ is cycloalkyl, heterocyclyl, aryl or heteroaryl;
R. ^2a , R ^2b and R ^2c is independently at each occurrence H, amino, cyano, halo, hydroxyl, C ₁ ～C ₆ alkyl, C ₁ ～C ₆ alkylamino, C ₁ ～C ₆ haloalkyl, C ₁ ～C ₆ Alkoxy, C ₁ ～C ₆ haloalkoxy; C ₃ ～C ₈ cycloalkyl, heterocyclylalkyl, C ₁ ～C ₆ alkynyl, C ₁ ～C ₆ alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
L is independently at each occurrence absent, -O-, -NR ^d -, -NR ^d C(=O)-,-NR ^d S (=O) ₂ - and -S (=O) ₂ is a linker selected from the group consisting of -, wherein R ^d is H or C ₁ ～C ₆ is alkyl;
L. ¹ is alkylene, heteroalkylene, heterocyclylene, aminylheterocyclylene
is alkylheterocyclylene or heteroalkylheterocyclylene;

indicates an aromatic ring; and
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the KRAS, HRAS or NRAS G12C mutant protein] or a pharmaceutically acceptable salt, isotopic form thereof , stereoisomers or prodrugs.
(Section 2)
The following structure (Ia):

2. The compound according to item 1 above, having
(Section 3)
L. ¹ is heterocyclylene, alkylheterocyclylene or heteroalkylheterocyclylene
3. The compound according to any one of the above items 1 or 2, which is rene.
(Section 4)
The following structure (Ib):

[In the formula,
G. ¹ and G ² are each independently N or CH with the proviso that G ¹ and G ² one of is N;
R. ^3a and R ^3b is independently at each occurrence H, —OH, —NH ₂ , -CO ₂ H, halo, cyano, C ₁ ～C ₆ alkyl, C ₁ ～C ₆ haloalkyl, C ₁ ～C ₆ haloalkoxy, C ₁ ～C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R ^3a and R ^3b together form an oxo, carbocyclic or heterocyclic ring; or R ^3a is H, -OH, -NH ₂ , -CO ₂ H, halo, cyano, C ₁ ～C ₆ alkyl, C ₁ ～C ₆ haloalkyl, C ₁ ～C ₆ haloalkoxy, C ₁ ～C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; ^3b is R ^4b together form a carbocyclic or heterocyclic ring;
R. ^4a and R ^4b is independently at each occurrence H, —OH, —NH ₂ , -CO ₂ H, halo, cyano, C ₁ ～C ₆ alkyl, C ₁ ～C ₆ haloalkyl, C ₁ ～C ₆ haloalkoxy, C ₁ ～C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R ^4a and R ^4b together form an oxo, carbocyclic or heterocyclic ring; or R ^4a is H, -OH, -NH ₂ , -CO ₂ H, halo, cyano, C ₁ ～C ₆ alkyl, C ₁ ～C ₆ haloalkyl, C ₁ ～C ₆ haloalkoxy, C ₁ ～C ₆ alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; ^4b is R ^3b together form a carbocyclic or heterocyclic ring; and
m ¹ and m ² are each independently 1, 2 or 3].
(Section 5)
Structure (Ic) below:

[In the formula,

represents a double or triple bond;
L. ² is a bond or alkylene;
Q is -C(=O)-, -C(=NR ⁷ )-,-NR ⁸ C(=O)-, -S(=O) ₂ - or - NR ⁸ S (=O) ₂ - is;

is a double bond, then R ⁵ and R ⁶ are each independently H, halo, cyano, carboxyl, C ₁ ～C ₆ is alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R ⁵ and R ⁶ together form a carbocyclic, heterocyclic or heteroaryl ring;

is a triple bond, then R ⁵ does not exist and R ⁶ is H, C ₁ ～C ₆ alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl;
R. ⁷ is H, —OH, —CN or C ₁ ～C ₆ is alkyl;
R. ⁸ is H, C ₁ ～C ₆ Alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C ₃ ～C ₈ is cycloalkyl or heterocyclylalkyl].
(Section 6)
The following structure (Id):

6. The compound according to item 5 above, which has
(Section 7)
m ¹ and m ² are both 1;
m ¹ and m ² are both 2; or
m ¹ is 2 and m ² 7. The compound according to any one of the above items 5 or 6, wherein is 1.
(Section 8)
G. ¹ and G ² are both N; or
G. ¹ is CH, and G ² is N. The compound according to any one of items 4 to 7 above.
(Section 9)
A is the following structure:

9. The compound according to any one of items 1 to 8, having one of
(Section 10)
The following structures (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip) , (Iq), (Ir), (Is), (It) or (Iu):

[In the formula, R ^2a is H or C ₁ ～C ₆ Item 5. The compound according to item 4, which has one of the following items: is alkyl.
(Item 11)
R. ¹ 11. The compound according to any one of the above items 1 to 10, wherein is aryl.
(Item 12)
R. ¹ 12. The compound according to item 11, wherein is phenyl or naphthyl.
(Item 13)
R. ¹ 11. The compound according to any one of the above items 1 to 10, wherein is heteroaryl.
(Item 14)
R. ¹ 14. The compound of claim 13, wherein contains nitrogen.
(Item 15)
R. ¹ 15. A compound according to any one of claims 13 or 14, wherein is indazolyl, indolyl, benzimidazole, benzotriazole or quinolinyl.
(Item 16)
R. ¹ 16. A compound according to any one of the preceding clauses 1-15, wherein is substituted with one or more substituents.
(Item 17)
R. ¹ is halo, hydroxyl, C ₁ ～C ₆ alkyl, cyano, C ₁ ～C ₆ haloalkyl, C ₁ ～C ₆ alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronic ester, -OC(=O)R or C ₁ ～C ₆ substituted with alkylcarbonyloxy or combinations thereof, wherein R is C ₁ ～C ₆ 17. The compound according to item 16, which is alkyl.
(Item 18)
R. ¹ 18. The compound according to item 17, wherein is substituted with fluoro, chloro, hydroxyl or methyl or a combination thereof.
(Item 19)
R. ¹ but the following structure:

19. The compound according to any one of the preceding clauses 1-18, having one of
(Section 20)
R. ¹ but the following structure:

20. The compound according to item 19, having one of
(Section 21)
R. ^a is independently at each occurrence H, cyano, -C(=O)NH ₂ ,

10. The compound according to any one of items 1 to 9 above.
(Section 22)
22. The compound according to any one of the above items 5 to 21, wherein Q is -C(=O)-.
(Section 23)
R. ⁵ and R ⁶ 23. The compound according to any one of items 5 to 22, wherein each is H.
(Section 24)
E is the following structure:

24. The compound according to any one of the preceding clauses 1-23, having one of
(Section 25)
E is

25. The compound according to item 24 above.
(Section 26)
L. ² 26. The compound according to any one of items 5 to 25, wherein is a bond.
(Section 27)
27. The compound according to any one of items 1 to 26, wherein L is absent.
(Section 28)
L is -O-, -NH-, -NHC(=O)-, -NHS(=O) ₂ - or -S (=O) ₂ 27. The compound according to any one of the above items 1 to 26, wherein -.
(Section 29)
R. ^3a , R ^3b , R ^4a and R ^4b 29. The compound according to any one of items 4 to 28, wherein each is H.
(Item 30)
R. ^3a , R ^3b , R ^4a or R ^4b 29. The compound of any one of clauses 4-28, wherein at least one occurrence of
(Item 31)
R. ^3a , R ^3b , R ^4a or R ^4b at least one occurrence of C ₁ ～C ₆ 29. The compound according to any one of the above items 4 to 28, which is alkyl.
(Item 32)
C. ₁ ～C ₆ 32. The compound according to item 31, wherein the alkyl is methyl.
(Item 33)
The structure below:

2. The compound of claim 1, having one of
(Item 34)
34. A substantially purified atropisomer according to any one of items 1 to 33 above.
(Item 35)
35. A pharmaceutical composition comprising a compound according to any one of items 1 to 34 above and a pharmaceutically acceptable carrier.
(Item 36)
36. The pharmaceutical composition according to Item 35, which is formulated for oral administration.
(Item 37)
36. The pharmaceutical composition according to Item 35, which is formulated for injection.
(Item 38)
A method for treating cancer, comprising the step of administering an effective amount of the pharmaceutical composition according to any one of items 35 to 37 to a subject in need of cancer treatment, Method.
(Item 39)
39. The method of paragraph 38, wherein said cancer is mediated by KRAS G12C, HRAS G12C or NRAS G12C mutations.
(Item 40)
40. The method of any one of Clauses 38 or 39, wherein the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer or lung cancer.
(Item 41)
35. A method for modulating the activity of a KRAS, HRAS or NRAS G12C mutant protein comprising reacting said KRAS G12C mutant protein with a compound of any one of clauses 1-34 above, Method.
(Item 42)
35. A method for inhibiting proliferation of a cell population, comprising contacting said cell population with a compound according to any one of clauses 1-34 above.
(Item 43)
43. The method of Clause 42, wherein inhibition of proliferation is measured as a decrease in cell viability of said cell population.
(Item 44)
A method for treating a disorder mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation in a subject in need thereof, comprising:
determining whether said subject has a KRAS, HRAS or NRAS G12C mutation; and
If said subject is determined to have said KRAS, HRAS or NRAS G12C mutation, administering to said subject a therapeutically effective amount of the pharmaceutical composition of any one of paragraphs 35-37 above. including, method.
(Item 45)
45. The method of Clause 44, wherein said disorder is cancer.
(Item 46)
46. The method of Clause 45, wherein the cancer is hematological cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer or lung cancer.
(Item 47)
35. A method for preparing a labeled KRAS, HRAS or NRAS G12C mutant protein, comprising reacting said KRAS, HRAS or NRAS G12C mutant with a compound of any one of claims 1-34, providing said labeled KRAS, HRAS or NRAS G12C protein.
(Item 48)
38. A method for inhibiting tumor metastasis, comprising the step of administering an effective amount of the pharmaceutical composition of any one of items 35 to 37 to a subject in need of inhibition of tumor metastasis, Method.

Claims (1)

The invention described in the specification .